Background:Mufangji tang(MFJT)is composed of Ramulus Cinnamomi,Radix Ginseng,Cocculus orbiculatus(Linn.)DC.,and Gypsum.In clinical settings,MFJT has been effectively employed in addressing a range of respiratory disor...Background:Mufangji tang(MFJT)is composed of Ramulus Cinnamomi,Radix Ginseng,Cocculus orbiculatus(Linn.)DC.,and Gypsum.In clinical settings,MFJT has been effectively employed in addressing a range of respiratory disorders,notably including pulmonary arterial hypertension(PAH).However,the mechanism of action of MFJT on PAH remains unknown.Methods:In this study,a monocrotaline-induced PAH rat model was established and treated with MFJT.The therapeutic effects of MFJT on PAH rat model were evaluated.Network pharmacology was conducted to screen the possible targets for MFJT on PAH,and the molecular docking between the main active components and the core targets was carried out.The key targets identified from network pharmacology were tested.Results:Results showed significant therapeutic effects of MFJT on PAH rat model.Analysis of network pharmacology revealed several potential targets related to apoptosis,inflammation,oxidative stress,and vascular remodeling.Molecular docking showed that the key components were well docked with the core targets.Further experimental validation results that MFJT treatment induced apoptosis(downregulated Bcl-2 levels and upregulated Bax levels in lung tissue),inhibited inflammatory response and oxdative stress(decreased the levels of IL-1β,TNF-α,inducible NOS,and malondialdehyde,and increased the levels of endothelial nitric oxide synthase,nitric oxide,glutathione and superoxide dismutase),reduced the proliferation of pulmonary arterial smooth muscle cells(downregulated ET-1 andβ-catenin levels and ERK1/2 phosphorylation,increased GSK3βlevels).Conclusion:Our study revealed MFJT treatment could alleviate PAH in rats via induction of apoptosis,inhibition of inflammation and oxidative stress,and the prevention of vascular remodeling.展开更多
Background Increasing research suggests that mitochondrial defect plays a major role in pulmonary hypertension(PH) pathogenesis. Mitochondrial dynamics and quality control have a central role in the maintenance of the...Background Increasing research suggests that mitochondrial defect plays a major role in pulmonary hypertension(PH) pathogenesis. Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation and apoptosis balance. However, the molecular mechanism underlying of this balance is still unknown. Methods To clarify the biological effects of hypoxic air exposure and hypoxia-inducible factor-1α(HIF-1α) on pulmonary arterial smooth muscle cell(PASMC) and pulmonary arterial hypertension rats, the cells were cultured in a hypoxic chamber under oxygen concentrations. Cell viability, reactive oxygen species level, cell death, mitochondrial morphology, mitochondrial membrane potential, mitochondrial function and mitochondrial biosynthesis, as well as fission-and fusion-related proteins, were measured under hypoxic conditions. In addition, rats were maintained under hypoxic conditions, and the right ventricular systolic pressure, right ventricular hypertrophy index and right ventricular weight/body weight ratio were examined and recorded. Further, we assessed the role of HIF-1α in the development and progression of PH using HIF-1α gene knockdown using small interfering RNA transfection. Mdivi-1 treatment was performed before hypoxia to inhibit dynamin-related protein 1(Drp1). Results We found that HIF-1α expression was increased during hypoxia, which was crucial for hypoxia-induced mitochondrial dysfunction and hypoxia-stimulated PASMCs proliferation and apoptosis. We also found that targeting mitochondrial fission Drp1 by mitochondrial division inhibitor Mdivi-1 was effective in PH model rats. The results showed that mitochondrial dynamics were involved in the pulmonary vascular remodeling under hypoxia in vivo and in vitro. Furthermore, HIF-1α also modulated mitochondrial dynamics in pulmonary vascular remodeling under hypoxia through directly regulating the expression of Drp1. Conclusions In conclusion, our data suggests that abnormal mitochondrial dynamics could be a marker for the early diagnosis of PH and monitoring disease progression. Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in PH.展开更多
BACKGROUND:Acute pulmonary embolism(APE)with cardiac arrest(CA)is characterized by high mortality in emergency due to pulmonary arterial hypertension(PAH).This study aims to determine whether early pulmonary artery re...BACKGROUND:Acute pulmonary embolism(APE)with cardiac arrest(CA)is characterized by high mortality in emergency due to pulmonary arterial hypertension(PAH).This study aims to determine whether early pulmonary artery remodeling occurs in PAH caused by massive APE with CA and the protective effects of increasing angiotensin-converting enzyme(ACE)2-angiotensin(Ang)(1-7)-Mas receptor axis and ACE-Ang II-Ang II type 1 receptor(AT1)axis(ACE2/ACE axes)ratio on pulmonary artery lesion after return of spontaneous circulation(ROSC).METHODS:To establish a porcine massive APE with CA model,autologous thrombus was injected into the external jugular vein until mean arterial pressure dropped below 30 mmHg(1 mmHg=0.133 kPa).Cardiopulmonary resuscitation and thrombolysis were delivered to regain spontaneous circulation.Pigs were divided into four groups of five pigs each:control group,APE-CA group,ROSC-saline group,and ROSC-captopril group,to examine the endothelial pathological changes and expression of ACE2/ACE axes in pulmonary artery with or without captopril.RESULTS:Histological analysis of samples from the APE-CA and ROSC-saline groups showed that pulmonary arterioles were almost completely occluded by accumulated endothelial cells.Western blotting analysis revealed a decrease in the pulmonary arterial ACE2/ACE axes ratio and increases in angiopoietin-2/angiopoietin-1 ratio and expression of vascular endothelial growth factor(VEGF)in the APE-CA group compared with the control group.Captopril significantly suppressed the activation of angiopoietin-2/angiopoietin-1 and VEGF in plexiform lesions formed by proliferative endothelial cells after ROSC.Captopril also alleviated endothelial cell apoptosis by increasing the B-cell lymphoma-2(Bcl-2)/Bcl-2-associated X(Bax)ratio and decreasing cleaved caspase-3 expression.CONCLUSION:Increasing the ACE2/ACE axes ratio may ameliorate pulmonary arterial remodeling by inhibiting the apoptosis and proliferation of endothelial cells after ROSC induced by APE.展开更多
BACKGROUND The accumulation of advanced glycation end products(AGEs)have been implicated in the development and progression of diabetic vasculopathy.However,the role of profilin-1 as a multifunctional actin-binding pr...BACKGROUND The accumulation of advanced glycation end products(AGEs)have been implicated in the development and progression of diabetic vasculopathy.However,the role of profilin-1 as a multifunctional actin-binding protein in AGEs-induced atherosclerosis(AS)is largely unknown.AIM To explore the potential role of profilin-1 in the pathogenesis of AS induced by AGEs,particularly in relation to the Janus kinase 2(JAK2)and signal transducer and activator of transcription 3(STAT3)signaling pathway.METHODS Eighty-nine individuals undergoing coronary angiography were enrolled in the study.Plasma cytokine levels were detected using ELISA kits.Rat aortic vascular smooth muscle cells(RASMCs)were incubated with different compounds for different times.Cell proliferation was determined by performing the MTT assay and EdU staining.An AGEs-induced vascular remodeling model was established in rats and histological and immunohistochemical analyses were performed.The mRNA and protein levels were detected using real-time PCR and Western blot analysis,respectively.In vivo,shRNA transfection was performed to verify the role of profilin-1 in AGEs-induced proatherogenic mediator release and aortic remodeling.Statistical analyses were performed using SPSS 22.0 software.RESULTS Compared with the control group,plasma levels of profilin-1 and receptor for AGEs(RAGE)were significantly increased in patients with coronary artery disease,especially in those complicated with diabetes mellitus(P<0.01).The levels of profilin-1 were positively correlated with the levels of RAGE(P<0.01);additionally,the levels of both molecules were positively associated with the degree of coronary artery stenosis(P<0.01).In vivo,tail vein injections of AGEs induced the release of proatherogenic mediators,such as asymmetric dimethylarginine,intercellular adhesion molecule-1,and the N-terminus of procollagen III peptide,concomitant with apparent aortic morphological changes and significantly upregulated expression of the profilin-1 mRNA and protein in the thoracic aorta(P<0.05 or P<0.01).Downregulation of profilin-1 expression with an shRNA significantly attenuated AGEs-induced proatherogenic mediator release(P<0.05)and aortic remodeling.In vitro,incubation of vascular smooth muscle cells(VSMCs)with AGEs significantly promoted cell proliferation and upregulated the expression of the profilin-1 mRNA and protein(P<0.05).AGEs(200μg/mL,24 h)significantly upregulated the expression of the STAT3 mRNA and protein and JAK2 protein,which was blocked by a JAK2 inhibitor(T3042-1)and/or STAT3 inhibitor(T6308-1)(P<0.05).In addition,pretreatment with T3042-1 or T6308-1 significantly inhibited AGEs-induced RASMC proliferation(P<0.05).CONCLUSION AGEs induce proatherogenic events such as VSMC proliferation,proatherogenic mediator release,and vascular remodeling,changes that can be attenuated by silencing profilin-1 expression.These results suggest a crucial role for profilin-1 in AGEs-induced vasculopathy.展开更多
OBJECTIVE To explore the role of calpain in in pulmonary vascular remodeling in hypoxia induced pulmonary hypertension and the underlying mechanism.METHODS Sprague-Dawley rats were randomly divided into hypoxia group ...OBJECTIVE To explore the role of calpain in in pulmonary vascular remodeling in hypoxia induced pulmonary hypertension and the underlying mechanism.METHODS Sprague-Dawley rats were randomly divided into hypoxia group and normoxia control group.Right ventricular systolic pressure(RVSP)and mean pulmonary artery pressure(m PAP)were monitored by the method of right external jugular vein cannula.Right ventricular hypertrophy index was expressed as the ratio of right ventricular weight to left ventricular weight(left ventricle plus septum weight).Level of calpain-1,calpain-2and calpain-4 m RNA in pulmonary artery trunk were determined by real-time PCR.Expression of calpain-1,calpain-2 and calpain-4 protein was determined by Western Blot.Primary rat pulmonary arterial smooth muscle cells(PASMCs)were divided into 4 groups:normoxia control group,normoxia+MDL28170 group,hypoxia group and hypoxia+MDL28170 group.Cell proliferation was detected by MTS and flow cytometry.Level of Ki-67 and PCNA m RNA were determined by real-time PCR.RESULTS RVSP,m PAP and right ventricular remodeling index were significantly higher in the hypoxia group than those in the normoxia group.In the hypoxia group,pulmonary vascular remodeling occurred,and the expression of calpain-1,calpain-2 and calpain-4 m RNA and protein expression was increased in the pulmonary artery.MDL28170 significantly inhibited hypoxia-induced proliferation of PASMCs accompanied with decreased Ki-67and PCNA m RNA expression.CONCLUSION Calpain mediated vascular remodeling via promoting proliferation of PASMCs in hypoxia induced pulmonary hypertension.展开更多
Objective:To evaluate the potential therapeutic effect of Sang-Yod rice bran hydrolysates(SRH)and in combination with lisinopril against hypertension,endothelial dysfunction,vascular remodeling,and oxidative stress in...Objective:To evaluate the potential therapeutic effect of Sang-Yod rice bran hydrolysates(SRH)and in combination with lisinopril against hypertension,endothelial dysfunction,vascular remodeling,and oxidative stress in rats with nitric oxide deficiency-induced hypertension.Methods:Hypertension was induced in male Sprague-Dawley rats by administration of a nitric oxide synthase inhibitor,Nω-nitro-L-arginine methyl ester(L-NAME)in drinking water for 6 weeks.Hypertensive rats were administered daily with SRH(500 mg/kg/day),lisinopril(1 mg/kg/day),or the combination of SRH and lisinopril by gastric lavage for the last 3 weeks of L-NAME treatment.Hemodynamic status,vascular reactivity to vasoactive agents,and vascular remodeling were assessed.Blood and aortic tissues were collected for measurements of oxidative stress markers,plasma angiotensin-converting enzyme(ACE)activity,plasma angiotensinⅡ,and protein expression.Results:L-NAME induced remarkable hypertension and severe oxidative stress,and altered contents of smooth muscle cells,elastin,and collagen of the aortic wall.SRH or lisinopril alone reduced blood pressure,restored endothelial function,decreased plasma ACEs and angiotensinⅡlevels,alleviated oxidant markers and glutathione redox status,and restored the vascular structure.The effects were associated with increased expression of endothelial nitric oxide synthase and decreased expression of gp91phox and AT1R expression.The combination of SRH and lisinopril was more effective than monotherapy.Conclusions:SRH alone or in combination with lisinopril exert an antihypertensive effect and improve endothelial function and vascular remodeling through reducing oxidative stress and suppressing elevated renin-angiotensin system.展开更多
Vascular remodeling,which can be found in atherosclerosis,restenosis after angioplasty,hypertension,and some other frequent and serious chronic diseases.Smooth muscle cell(SMC)phenotype change,which has been described...Vascular remodeling,which can be found in atherosclerosis,restenosis after angioplasty,hypertension,and some other frequent and serious chronic diseases.Smooth muscle cell(SMC)phenotype change,which has been described as converting from a contractile state into a synthetic phenotype,is a crucial event during vascular remodeling.Recently,micro RNAs(mi RNAs)a kind of small non-coding RNA molecules,has been proven to target critical genes of cell signaling pathways to regulate SMC phenotypic change.By searching the Pub Med,Embase,reviews,and reference listsof relevant papers,we systematically carried out a review of the literature to provide an overview of the mi RNAs and their target genes in cell signaling pathways,focus inthe pathways involving in SMC phenotype change.To be specific,mi RNAs that regulate genes involved in the MAPK signaling pathways(such as:mi R-155,mi R-92a,mi R-424/503,mi R-133,mi R-181b,mi R-31,mi R-1298,mi R-132,mi R-200c and mi R-483-3p),mi RNAs target genes involved in the TGF-βsignaling pathways(including mi R-24,mi R-17/92 cluster,mi R-599,mi R-21 and mi R-143/145),mi RNAs target the genes involved in the AMPK signaling pathways including mi R-144/451 and mi R-195,mi RNAs target the genes involved in the PI3K-Akt signaling pathways(including mi R-138,mi R-34c,mi R-223,mi R-761,mi R-10a,mi R-146a),mi R-199a-5ptargets the genes involved in the Wnt signaling pathways mi RNAs(mi R-221/222,mi R-15b,mi R-24/29a,mi R-224)involved in the PDGF signaling pathways and some mi RNAs(mi R-638,mi R-328,mi R-365,mi R-663,mi R-29b,mi R-130,mi R-142-5p,mi R-424/322)which regulate SMC phenotype change by other corresponding targets were in detailed discussed in our review.Exploring the regulation of miR NAs in key cellsignaling pathways-mediatedvascular remodeling wil have momentous impact on identifying novel therapeutic targets for its associated disease.展开更多
Objective: To investigate the bioactive components of Sangqi Qingxuan formula(SQQX), predict the pharmacological targets, and explore the mechanism of hypertensive vascular remodeling(HVR).Methods: Network pharmacolog...Objective: To investigate the bioactive components of Sangqi Qingxuan formula(SQQX), predict the pharmacological targets, and explore the mechanism of hypertensive vascular remodeling(HVR).Methods: Network pharmacology was adopted to predict how SQQX acts in HVR. The effectiveness was assessed by blood pressure measurements and pathological morphology observation based on a spontaneously hypertensive rat model, while the mechanism of SQQX on HVR was validated by immunohistochemistry(IHC) and western blot(WB) according to the results of network pharmacology.Results: There were 130 bioactive components of SQQX and 231 drug targets predicted by the Traditional Chinese Medicine Systems Pharmacology Database. Subsequently, 181 common targets were identified for SQQX against HVR, with TP53, MAPK1, and AKT1 as the core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses was employed to identify the top 20 enriched functions and the top 20 pathways(P <.01). Finally, the key role of the ERK/MAPK signaling pathway in HVR was determined. The in vivo results suggested that SQQX reduced systolic blood pressure and increased the ratio of thoracic aortic wall thickness to lumen diameter. Additionally, compared with the model group, SQQX increased the expression of smooth muscle 22 alpha(IHC: P <.001;WB:P <.05) and decreased the expression of osteopontin(IHC: P <.001;WB: P <.05), ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), p-ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), and the ratio of pERK1/2 to ERK1/2 protein(IHC: P <.001).Conclusions: SQQX, which has multiple bioactive ingredients and potential targets, is an effective treatment for HVR. The mechanism of antihypertensive and vascular protection may be related to the inhibition of phenotypic transformation of vascular smooth muscle cells and the ERK/MAPK signaling pathway.展开更多
Pathological vascular remodeling is characterized by thickening or thinning of the vessel wall through altering cellular and non-cellular components,which associates with various blood circulation disorders in brain,h...Pathological vascular remodeling is characterized by thickening or thinning of the vessel wall through altering cellular and non-cellular components,which associates with various blood circulation disorders in brain,heart,lung,and peripheral vasculatures. Pathological vascular remodeling occurs in response to a variety of vascular insults such as mechanical(angioplasty or stenting) or biological(lipids,diabetes,smoking,or virus) injuries. It is a polygenic process involving multiple cell types in the vessel wall or circulation,including endothelial cells(ECs),smooth muscle cells(SMCs),fibroblasts,leukocytes,and platelets. One of hallmarks is the transition of vascular smooth muscle cells(SMCs)from a differentiated/quiescent contractile phenotype to a myofibroblast-like dedifferentiated/active so-called synthetic phenotype. Synthetic SMCs are proliferatory,migratory,secretory and inflammatory,playing key roles in the pathogenesis of vascular remodeling. In the normal vessel,ECs synthesize and secrete biological substances such as prostacyclins(PGI_2) and nitric oxide(NO) that not only function as vasodilators but also inhibit SMC phenotype transition and other properties associated with the synthetic phenotype. Cyclic nucleotides cAMP and cGMP are primary mediators of PGI_2 and NO,respectively,and play critical roles in control vascular structural integrity and function. Cyclic nucleotides are controlled by selective activation or inhibition of distinct cyclic nucleotide phosphodiesterase(PDE) isozymes catalyzing the degradation reaction. To date,more than 60 different PDE isoenzymes derived from 22 genes are identified and grouped into 11 broad families(PDE1-PDE11). PDEs are expressed in a cell/tissue-specific manner and only a few enzymes are expressed in any single cell type. Through systematic assessment of the expression levels of all known PDE isoforms in contractile versus synthetic SMCs,we found that the expression levels of a number of PDE are significantly altered between two SMC phenotypes. We then explored the functional roles and underlying mechanisms of these altered PDEs in vascular SMCs pathogenesis and vascular remodeling in vitro and in vivo using a variety of gain-of-or loss-of-function approaches. For example,we found that Ca^(2+)/calmodulinstimulated cAMP/cGMP-hydrolyzing PDE 1C is selectively expressed in synthetic SMCs in vitro and in various vascular disease models in vivo. PDE 1C upregulation contributes to a number of pathogenic functions of synthetic SMCs,such as cell proliferation,migration,and matrix protein metabolism.PDE 1C deficiency markedly attenuates intimal hyperplasia,atherosclerosis,and aortic aneurysm in experimental mouse disease models. These findings suggest that PDE 1C functions as a key regulator of the synthetic SMC pathology in vascular remodeling. Inhibiting PDE 1C function may represent a novel therapeutic strategy for protecting against the pathogenesis of vascular diseases.展开更多
The current study revealed that increased synthesis and secretion of collagen types I and III play major roles in arterial wall remodeling, aneurysm formation, and atherosclerotic cap stability. The aim is to investig...The current study revealed that increased synthesis and secretion of collagen types I and III play major roles in arterial wall remodeling, aneurysm formation, and atherosclerotic cap stability. The aim is to investigate the age-related changes of the procollagen alpha polypeptide gene mRNA and protein expression in the vascular smooth muscle cells (VSMCs) in rats, as well as the possible underlying mechanisms. We tested in vitro culture of VSMC from the thoracoabdominal aorta in neonate and 9-month-old healthy male Wistar rats;procollagen alpha polypeptide mRNA and procollagen alpha polypeptide protein expression were detected, using RT-PCR, VG staining, Western blot and ELISA methods. Semi-quantitative analysis displayed that, in the real-time reverse transcription polymerase chain reaction (RT-PCR), the type I collagen α polypeptide chain mRNA increased in the adult group, but not significantly (<em>P</em> = 0.05). Further, there was no significant difference between the two groups of type III collagen α polypeptide chain mRNA (<em>P</em> > 0.05). Both the type I and type III procollagen alpha polypeptide protein expression were increased significantly in the older group as compared with the young group (<em>P</em> < 0.05). This phenomenon mainly lies in the fact that the regulatory pathway on age-related changes of procollagen alpha polypeptides may be one of the molecular mechanisms in vascular remodeling during aging.展开更多
Objective: To investigate the structural changes of aorta, and evaluate the effects of atorvastatinon the remodeling of thoracic aorta in spontaneously hypertensive rats(SHR) . Methods : Twelve eight-week-old SHR were...Objective: To investigate the structural changes of aorta, and evaluate the effects of atorvastatinon the remodeling of thoracic aorta in spontaneously hypertensive rats(SHR) . Methods : Twelve eight-week-old SHR were randomized into atorvastatin treated group( ATV group, n = 6) and distilled water group( DW group, n = 6) ; Wistar-Kyoto rats(WKY) were used as normal controls. Atorvastatin was administered to ATV group for 10 weeks by gavage in mixture with distilled water( 1ml) ; the latter two groups were given the same amount of distilled water by gavage for 10 weeks. Systolic blood pressure of caudal artery was examined before and after treatment, and serum concentrations of total cholesterol, triglycerides and HDL-C were measured.Wall thickness, media thickness, medial cross-sectional area and lumen diameter of thoracic aorta were assessed with computed video processing. Results: Systolic blood pressure in ATV group was markedly lower than that in DW group( P < 0.01). Compared with DW group and WKY group, serum concentrations of total cholesterol, triglycerides and HDL-C in ATV group were significantly lower( P < 0.01, P < 0.05). Wall thickness, media thickness, and medial cross-sectional area to lumen ratio in DW group were significantly higher than those in WKY group and ATV group( P < 0.01, P < 0.05), but no such difference was found between WKY group and ATV group( P > 0.05 ). Conclusion : Vascular structural changes of aorta are due to the alteration of the vessel wall in early stage of SHR. Atorvastatin can markedly improve vascular remodeling.展开更多
We investigated the expression of heme oxygenase 1 (HO 1) gene and production of endogenous carbon monoxide (CO) in the rat lung tissue at different time points of chronic hypoxic pulmonary hypertension and the effect...We investigated the expression of heme oxygenase 1 (HO 1) gene and production of endogenous carbon monoxide (CO) in the rat lung tissue at different time points of chronic hypoxic pulmonary hypertension and the effect of hemin on the expression of HO 1 gene and pulmonary hypertension. A rat model of hypoxic pulmonary hypertension was recreated by exposure to intermittent normobaric hypoxic environment (10 % O 2). Reverse transcriptase polymerase chain reaction (RT PCR) was performed to determine the level of HO 1 mRNA in the rat lung tissue and double wave length spectrophotometry was used to evaluate the quantity of COHb in arterial blood. Cardiac catheterization was employed to measure the right ventricular systolic pressure (RVSP) and HE staining was performed in dissected lung tissue to observe the pathological changes of the intra acinar pulmonary arteries (IAPA). It was found that (1) There was a low level of HO 1 mRNA in normal rat lung tissue, but the level of HO 1 mRNA increased by 2-4 times in the lung tissue of hypoxic rats ( P <0.01). The quantity of COHb was 2-3 times those of control group ( P <0.01 or P <0.05). These were accompanied by the increased of RVSP and the thickened IAPA; (2) Hemin could keep the HO 1 mRNA and COHb in the hypoxic rat lung tissue at a high level, and partially suppressed the increase of rat RVSP, thereby ameliorating the pathological changes of IAPA. In conclusion, the upregulation of the expression of HO 1 gene and production of CO in the rat lung of hypoxic pulmonary hypertension plays a role of inhibition in the development of hypoxic pulmonary hypertension. Hemin has a therapeutic effect on hypoxic pulmonary hypertension.展开更多
Asymptomatic organ damage due to progressive kidney damage, cardiac hypertrophy and remodeling put hypertensive patients at high risk for developing heart and renal failure, myocardial infarction and stroke. Current a...Asymptomatic organ damage due to progressive kidney damage, cardiac hypertrophy and remodeling put hypertensive patients at high risk for developing heart and renal failure, myocardial infarction and stroke. Current antihypertensive treatment normalizes high blood pressure, partially reverses organ damage, and reduces the incidence of heart and renal failure. Activation of the renin-angiotensin system(RAS) is a primary mechanism of progressive organ damage and, specifically, a major cause of both renal and cardiovascular fibrosis. Currently, inhibition of the RAS system [mainly with angiotensin I converting enzyme inhibitors or angiotensin II(Ang II) receptor antagonists] is the most effective antihypertensive strategy for normalizing blood pressure and preventing target organ damage. However, residual organ damage and consequently high risk for cardiovascular events and renal failure still persist. Accordingly, in hypertension, it is relevant to develop new therapeutic perspectives, beyond reducing blood pressure to further prevent/reduce target organ damage by acting on pathways that trigger and maintain cardiovascular and renal remodeling. We review here relevant novel mechanisms of target organ damage in hypertension, their role and evidence in prevention/regression of cardiovascular remodeling and their possible clinical impact as well. Specifically, we focus on the signaling pathway Rho A/Rho kinase, on the impact of the vasodilatory peptides from the RAS and some insights on the role of estrogens and myocardial chymase in cardiovascular hypertensive remodeling.展开更多
The objective of this study was to evaluate the effects of low ambient temperature(LAT) and dietary vitamin C(VC)supplementation on pulmonary vascular remodeling(PVR) and the relative expression of hypoxia inducible f...The objective of this study was to evaluate the effects of low ambient temperature(LAT) and dietary vitamin C(VC)supplementation on pulmonary vascular remodeling(PVR) and the relative expression of hypoxia inducible factor-1α(HIF-1α),vascular endothelial growth factor(VEGF) and its receptor 2(VEGFR-2) mRNA of lungs in 21-d-old broilers.4001-d-old male Cobb broilers were assigned randomly to 4 treatments as follows for 21 d:1) LAT and a basal diet;2) LAT and a basal diet supplemented with 1 000 mg kg^(-1) VC(LAT+VC);3) normal ambient temperature(NAT) and a basal diet;4) NAT and a basal diet supplemented with 1 000 mg kg^(-1) VC(NAT+VC).Each treatment was composed of 10 replicates of 10 birds per replicate.Samples of lung were collected after the broilers were killed at d 21.LAT increased the ratio of vessel wall area to vessel total area(WA/TA,%) and mean media thickness in pulmonary arterioles(mMTPA,%)(P<0.05).Dietary VC supplementation decreased mMTPA(P<0.05),but had no effect on the WA/TA.LAT increased(P<0.05) the relative mRNA expression of HIF-1α,VEGF and VEGFR-2,while adding VC to the diet could decrease(P<0.05) their relative mRNA expression.A significant positive correlation existed between the level of VEGF mRNA expression and the value of WA/WT(P<0.05) or mMTPA(P<0.05).These results suggested LAT resulted in pulmonary vascular remodeling,and the increase of HIF-1a,VEGF and VEGFR-2 mRNA expression,and dietary VC supplementation can alleviate pulmonary vascular remodeling in broiler by affecting these gene expression.展开更多
Vascular remodeling is the essential pathogenic process of various cardiovascular disorders,including hypertension,atherosclerosis,stroke,and restenosis after vein graft.The main characterization of vascular remodelin...Vascular remodeling is the essential pathogenic process of various cardiovascular disorders,including hypertension,atherosclerosis,stroke,and restenosis after vein graft.The main characterization of vascular remodeling is abnormal variations of vascular cell phenotype,morphological structure and functions such as migration,hypertrophy,proliferation and apoptosis.Numerous researches revealed that mechanical stress,including shear stress and cyclic stretch,participates in physiological vascular homeostasis,or pathophysiological vascular remodeling.The understanding of mechanobiological mechanism in vascular remodeling will play a unique role in understanding human physiology and disease,and will generate important theoretical and clinical significance [2].Non-coding RNAs are newly recognized RNAs which cannot be translated into proteins but are involved in epigenetic modification of gene regulation.The studies revealed that non-coding RNAs,such as microRNAs(miRNAs)and long noncoding RNAs(long ncRNAs,IncRNA),as well as small interfering RNAs(siRNAs),piwi-interacting RNAs(piRNAs),small nucleolar RNAs(snoRNAs),play essential roles in the regulation of various processes,such as metabolism,development,cell proliferation,cell apoptosis,cell differentiation,oncogenesis and vascular homeostasis[5].However,the roles of non-coding RNAs in the cardiovascular system under mechanical stresses are still not clarified.Our recent researches detected the mechanical regulation of IncRNAs and miRNAs in vascular remodeling.LncRNAs are non-protein-coding transcripts that are longer than 200 nucleotides(nt),which is an arbitrary cut-off value that distinguishes these transcripts from other small RNAs.Unlike the well-established mechanism of microRNA action,the functional mode of IncRNAs is not fully understood.Increasing evidence shows that IncRNAs modulate gene expression via a multilevel-regulated pathway.Given their large number and complicated functional modes,lncRNAs are emerging as important regulators of a variety of cellular responses,developmental processes and diseases.Using a gene microarray,we screened the differences in the IncRNAs and mRNAs between spontaneously hypertensive rats(SHR)and Wistar Kyoto rats(WKY).The results showed that 68 IncRNAs and 255 mRNAs were up-regulated in the aorta of SHR,while 167 IncRNAs and 272 mRNAs were down-regulated.Expressions of the screened IncRNAs,including XR007793,were validated by real-time PCR.A co-expression network was composed,and gene function was analysed using Ingenuity Pathway Analysis.In vitro,vascular smooth muscle cells(VSMCs)were subjected to cyclic stretch at a magnitude of 5%(physiological normotensive cyclic stretch)or 15%(pathological hypertensive cyclic stretch)by Flexercell-5000TM.15%-cyclic-stretch increased XR007793 expression.XR007793 knockdown attenuated VSMC proliferation and migration and inhibited co-expressed genes such as signal transducers and activators of transcription 2(stat2),LIM domain only 2(lmo2)and interferon regulatory factor 7(irf7)[4].Illuminating the role of IncRNAs in vascular remodeling induced by hyper mechanical stretch may provide deeper insight into the mechanobiological mechanism underlying hypertension,and contribute to identifying potential targets for hypertension therapy.miRNAs are endogenous,non-coding,single-stranded RNAs of 18-22 nucleotides that constitute a novel class of gene regulators.miRNAs bind to their target genes within their 3’-untranslated regions(3’-UTRs),leading to direct degradation of mRNA or translational repression by a complete,i.e.in plants,or incomplete,i.e.in animals,complement respectively.Our resent works revealed several important mechano-responsive miRNA and their potential effects in vascular remodeling.Forexample,miRNA-33 is regulated by cyclic stretch in the grafted vessels,which targets to BMP3 and subsequent modulates smad signaling pathway.The miRNA-33-BMP3-smad pathway protects against venous VSMC proliferation in response to arterial cyclic stretch.Therefore,miRNA-33 may be a potential therapeutic target in autologous vein grafted surgery,and locally overexpression of miR-33 may attenuates neointimal hyperplasia of grafted human saphenous vein [3].The unpublished data revealed that 15%cyclic stretch also significantly elevated the expression of miRNA-124-3p which bound to the 3’UTR of Lmna mRNA,and then negatively regulated protein expression of lamin A/C which is the important skeletal proteins in nucleus.In addition to primary intracellular locations of miRNAs,our recent study showed that miRNAs can be secreted and protected extracellularly via inclusion into membrane-derived vesicles including microparticles.Microparticles are extracellular vesicles ranging from 0.1 to 1μm in size and have been shown to deliver various bioactive molecules,i.e.,chemokines,enzymes and miRNAs,to recipient cells.Increasing evidence shows that microparticles play a pivotal role in many pathological processes,such as cancer,inflammatory diseases and cardiovascular disease.Our present study showed that platelet-derived microparticles(PMPs),which are released by active platelets,are important vehicles for communication and play crucial roles in inducing abnormal EC proliferation in hypertension.In briefly,EC proliferation was increased in renal hypertensive rats established by abdominal aortic coarctation compared to control rats and that elevated thrombin in plasma promoted platelet activation,which may induce the release of PMPs.miRNA array and qPCR revealed a higher level of miRNA-142-3p in platelets and PMPs.In vitro,PMPs delivered miRNA-142-3p into ECs and enhanced EC proliferation via Bcl-2-associated transcription factor 1(BCLAF1)and its downstream genes.These results indicated that PMPs deliver miRNA-142-3p from activated platelets into ECs and that miRNA-142-3p may play important roles in EC dysfunction under hypertensive conditions and might be a novel therapeutic target for maintaining EC homeostasis in hypertension[1].These results provide possible mechanisms by which non-coding RNAs regulate cellular functions under different mechanical stresses,and suggest a novel potential therapeutic approach for vascular remodeling.The further studies on noncoding RNAs may provide new insight into understanding the mechanism of vascular remodeling in different various cardiovascular disorders,and may provide novel targets for the maintenance of vascular homeostasis.展开更多
Intravenous and intratracheal implantation of mesenchymal stem cells (MSCs) may offer ameliorating effects on pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats. The aim of this study was to examine th...Intravenous and intratracheal implantation of mesenchymal stem cells (MSCs) may offer ameliorating effects on pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats. The aim of this study was to examine the anti-remodeling effect of intravenous MSCs (VMSCs) and intratracheal MSCs (TMSCs) in rats with PH, and the underlying mechanisms. MSCs were isolated from rat bone marrow and cultured. PH was induced in rats by intraperitoneal injection of MCT. One week after MCT administration, the rats were divided into 3 groups in terms of different treatments: VMSCs group (intravenous injection of MSCs), TMSCs group (intratracheal injection of MSCs), PH group (no treatment given). Those receiving saline instead of MCT served as negative control (control group). Pulmonary arterial structure was pathologically observed, pulmonary arterial dynamics measured, and remodeling-associated cytokines Smad2 and Smad3 detected in the lungs, three weeks after MCT injection. The results showed that PH group versus control group had higher pulmonary arterial pressure (PAP) and wall thickness index (WTI) 21 days after MCT treatment. The expression of phosphorylated (p)-Smad2 and the ratio of p-Smad2/Smad2 were much higher in PH group than in control group. Fluorescence-labeled MSCs were extensively distributed in rats' lungs in VMSCs and TMSCs groups 3 and 14 days after transplantation, but not found in the media of the pulmonary artery. WTI and PAP were significantly lower in both VMSCs and TMSCs groups than in PH group three weeks after MCT injection. The p-Smad2 expression and the ratio of p-Smad2/Smad2 were obviously reduced in VMSCs and TMSCs groups as compared with those in PH group. In conclusion, both intravenous and intratracheal transplantation of MSCs can attenuate PAP and pulmonary artery remodeling in MCT-induced PH rats, which may be associated with the early suppression of Smad2 phosphorylation via paracrine pathways.展开更多
This study investigated the potential role of ERK1/2-cyclinE1 signaling pathway in rat pulmonary artery smooth muscle cells (rPASMCs) proliferation and pulmonary vascular remodeling induced by cigarette smoke exposure...This study investigated the potential role of ERK1/2-cyclinE1 signaling pathway in rat pulmonary artery smooth muscle cells (rPASMCs) proliferation and pulmonary vascular remodeling induced by cigarette smoke exposure. A total of 24 male Wistar rats were randomly divided into 4 groups: control group (C group), S-1M, S-3M and S-6M groups (animals in the groups were exposed to smoke for 1, 3, and 6 months, respectively). HE staining and anti-α-smooth muscle actin antibody staining were performed to observe the degree of pulmonary vascular remodeling. Immunohistochemis- try and Western blotting were performed to evaluate ERK1/2 and cyclinE1 expression in pulmonary vessels. Primary cultured rat pulmonary artery smooth muscle cells (rPASMCs) were exposed to ciga- rette smoke extract (CSE). ERK inhibitor (PD98059) and cyclinE1 siRNA were used to verify the role of ERK1/2 and cyclinE1 in CSE-induced rPASMCs proliferation. Cell proliferation was assessed by cell counting and 5-bromo-2-deoxyuridine (BrdU) incorporation. Our results showed that abnormal pulmo- nary vascular remodeling was found in cigarette smoked rats. Compared to C group, activated ERK1/2 and cyclinE1 expression was significantly increased in smoke-exposure groups. This up-regulated ex- pression was positively correlated with the severity of pulmonary vascular remodeling, and there was positive correlation between the expression of ERK1/2 and cyclinE1. PD98059 and cyclinE1 siRNA in- hibited the proliferation of rPASMCs. The expression of cyclinE1 could be down-regulated by PD98059. Our data demonstrated that increased expression of ERK1/2 and cyclinE1 might be involved in the pathogenesis of abnormal rPASMCs proliferation and rat pulmonary vascular remodelling induced by cigarette smoke exposure.展开更多
OBJECTIVE The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling,which is characteristic of pulmonary arterial hypertension(PAH).In this study we exam-ined whether s...OBJECTIVE The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling,which is characteristic of pulmonary arterial hypertension(PAH).In this study we exam-ined whether salvianolic acid A(SAA)extracted from the traditional Chinese medicine′Dan Shen′attenuated vascular remodeling in a PAH rat model,and elucidated the underlying mechanisms.METHODS PAH was induced in rats by injecting a single dose of monocrotaline(MCT 60 mg·kg-1,sc).The rats were orally treated with either SAA(0.3,1,3 mg·kg-1·d-1)or a positive control bosentan(30 mg·kg-1·d-1)for 4 weeks.Echocardiography and hemodynamic measurements were performed on d 28.Then the hearts and lungs were harvested,the organ indices and pulmonary artery wall thickness were calculated,and biochemical and histochemical analysis were conducted.The levels of apoptotic and signaling proteins in the lungs were measured using immunoblotting.RESULTS Treatment with SAA or bosentan effectively ameliorated MCTinduced pulmonary artery remodeling,pulmonary hemodynamic abnormalities and the subsequent increases of right ventricular systolic pressure(RVSP).Furthermore,the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium,parenchymal injury and collagen deposition in the lungs.Moreover,the treatments attenuated MCT-induced apoptosis and fibrosis in the lungs.The treatments partially restored MCT-induced reductions of bone morphogenetic protein typeⅡreceptor(BMPRⅡ)and phosphorylated Smad1/5 in the lungs.CONCLUSION SAA ameliorates the pulmonary arterial remodeling in MCT-induced PAH rats most likely via activating the BMPRⅡ-Smad pathway and inhibiting apoptosis.Thus,SAA may have therapeutic potential for the patients at high risk of PAH.展开更多
In order to investigate the effects of puerarin on pulmonary vascular remodeling and protein kinase C-α (PKC-α) in chronic exposure smoke rats, 54 male Wistar rats were randomly di-vided into 7 groups: control group...In order to investigate the effects of puerarin on pulmonary vascular remodeling and protein kinase C-α (PKC-α) in chronic exposure smoke rats, 54 male Wistar rats were randomly di-vided into 7 groups: control group (C group), smoke exposure groups (S4w group, S8w group), puer-arin groups (P4w group, P8w group), propylene glycol control groups (PC4w group, PC8w group). Rats were exposed to cigarette smoke or air for 4 to 8 weeks. Rats in puerarin groups also received puer-arin. To evaluate vascular remodeling, alpha-smooth muscle actin (α-SM-actin) staining was used to count the percentage of completely muscularised vessels to intraacinar pulmonary arteries (CMA/IAPA) which was determined by morphometric analysis of histological sections. Pulmonary artery smooth muscle cell (PASMC) apoptosis was detected by in situ end labeling technique (TUNEL), and proliferation by proliferating cell nuclear antigen (PCNA) staining. Reverse transcrip-tion-polymerase chain reaction (RT-PCR), immunofluorescence staining and Western blot analysis were done to detect the PKC-α mRNA and protein expression in pulmonary arteries. The results showed that in cigarette smoke-exposed rats the percentage of CMA/IAPA and α-SM-actin expres-sion were increased greatly, PASMC apoptosis was increased and proliferation was markedly in-creased; Apoptosis indices (AI) and proliferation indices (PI) were higher than in C group; AI and PI were correlated with vascular remodeling indices; The expression of PKC-α mRNA and protein in pulmonary arteries was significantly higher than in C group. In rats treated with puerarin, the per-centage of CMA/IAPA and cell proliferation was reduced, whereas PASMC apoptosis was increased; The expression levels of PKC-α mRNA and protein were lower than in smoke exposure rats. There was no difference among all these data between S groups and PC groups. These findings suggested that cigarette smoke-induced pulmonary vascular remodeling was most likely an effect of the imbal-ance of PASMC proliferation and apoptosis. Puerarin appears to be able to reduce cell proliferation and vascular remodeling possibly through PKC signaling transduction pathway.展开更多
Objective: To study the effects of serum Fractalkine on vascular remodeling and oxidative stress activation in patients with COPD complicated by pulmonary heart disease. Methods:Patients who were hospitalized in Chong...Objective: To study the effects of serum Fractalkine on vascular remodeling and oxidative stress activation in patients with COPD complicated by pulmonary heart disease. Methods:Patients who were hospitalized in Chongqing Armed Corps Police Hospital due to COPD between June 2014 and April 2017 were selected, the patients with COPD alone were included in COPD group, and the patients with COPD complicated by pulmonary heart disease were included in COPD+PHD group;healthy volunteers who underwent physical examination during the same period were selected as the control group of the study. The serum was collected to determine the contents of Fractalkine, vascular remodeling indexes and oxidative stress indexes. Results: Serum Fractalkine, ANG-2, MMP2, MMP9, VEGF, FGF2, Nogo-B, ET-1 and MDA contents of COPD+PHD group and COPD group were higher than those of control group whereas T-AOC contents were lower than that of control group;serum Fractalkine, ANG-2, MMP2, MMP9, VEGF, FGF2, Nogo-B, ET-1 and MDA contents of COPD+PHD group were higher than those of COPD group whereas T-AOC content was lower than that of COPD group. Serum ANG-2, MMP2, MMP9, VEGF, FGF2, Nogo-B, ET-1 and MDA contents of COPD+PHD group of patients with high Fractalkine content were significantly higher than those of COPD+PHD group of patients with low Fractalkine content whereas T-AOC content was lower than that of COPD+PHD group of patients with low Fractalkine content. Conclusion: The increase of serum Fractalkine in patients with COPD complicated by pulmonary heart disease can aggravate the vascular remodeling and promote the oxidative stress activation.展开更多
基金supported by the Qingdao Medical Research Guidance Plan(2020-WJZD049).
文摘Background:Mufangji tang(MFJT)is composed of Ramulus Cinnamomi,Radix Ginseng,Cocculus orbiculatus(Linn.)DC.,and Gypsum.In clinical settings,MFJT has been effectively employed in addressing a range of respiratory disorders,notably including pulmonary arterial hypertension(PAH).However,the mechanism of action of MFJT on PAH remains unknown.Methods:In this study,a monocrotaline-induced PAH rat model was established and treated with MFJT.The therapeutic effects of MFJT on PAH rat model were evaluated.Network pharmacology was conducted to screen the possible targets for MFJT on PAH,and the molecular docking between the main active components and the core targets was carried out.The key targets identified from network pharmacology were tested.Results:Results showed significant therapeutic effects of MFJT on PAH rat model.Analysis of network pharmacology revealed several potential targets related to apoptosis,inflammation,oxidative stress,and vascular remodeling.Molecular docking showed that the key components were well docked with the core targets.Further experimental validation results that MFJT treatment induced apoptosis(downregulated Bcl-2 levels and upregulated Bax levels in lung tissue),inhibited inflammatory response and oxdative stress(decreased the levels of IL-1β,TNF-α,inducible NOS,and malondialdehyde,and increased the levels of endothelial nitric oxide synthase,nitric oxide,glutathione and superoxide dismutase),reduced the proliferation of pulmonary arterial smooth muscle cells(downregulated ET-1 andβ-catenin levels and ERK1/2 phosphorylation,increased GSK3βlevels).Conclusion:Our study revealed MFJT treatment could alleviate PAH in rats via induction of apoptosis,inhibition of inflammation and oxidative stress,and the prevention of vascular remodeling.
基金supported by the National Natural Science Foundation of China (No. 81673858, No. 81704062, No. 30500644)the Science and Technology Project of Traditional Chinese Medicine in Hunan (No. 2009045, No. 2012027)the Program for National Center for Clinical Medicine for Geriatric Diseases (Ministry of Science and Technology)
文摘Background Increasing research suggests that mitochondrial defect plays a major role in pulmonary hypertension(PH) pathogenesis. Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation and apoptosis balance. However, the molecular mechanism underlying of this balance is still unknown. Methods To clarify the biological effects of hypoxic air exposure and hypoxia-inducible factor-1α(HIF-1α) on pulmonary arterial smooth muscle cell(PASMC) and pulmonary arterial hypertension rats, the cells were cultured in a hypoxic chamber under oxygen concentrations. Cell viability, reactive oxygen species level, cell death, mitochondrial morphology, mitochondrial membrane potential, mitochondrial function and mitochondrial biosynthesis, as well as fission-and fusion-related proteins, were measured under hypoxic conditions. In addition, rats were maintained under hypoxic conditions, and the right ventricular systolic pressure, right ventricular hypertrophy index and right ventricular weight/body weight ratio were examined and recorded. Further, we assessed the role of HIF-1α in the development and progression of PH using HIF-1α gene knockdown using small interfering RNA transfection. Mdivi-1 treatment was performed before hypoxia to inhibit dynamin-related protein 1(Drp1). Results We found that HIF-1α expression was increased during hypoxia, which was crucial for hypoxia-induced mitochondrial dysfunction and hypoxia-stimulated PASMCs proliferation and apoptosis. We also found that targeting mitochondrial fission Drp1 by mitochondrial division inhibitor Mdivi-1 was effective in PH model rats. The results showed that mitochondrial dynamics were involved in the pulmonary vascular remodeling under hypoxia in vivo and in vitro. Furthermore, HIF-1α also modulated mitochondrial dynamics in pulmonary vascular remodeling under hypoxia through directly regulating the expression of Drp1. Conclusions In conclusion, our data suggests that abnormal mitochondrial dynamics could be a marker for the early diagnosis of PH and monitoring disease progression. Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in PH.
基金supported by grants from the National Natural Science Foundation of China(81773931 and 81374004)the Beijing Municipal Administration of Hospitals’Youth Program(QML20170105)+1 种基金the Natural Science Foundation of Beijing Municipality(7173253)the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support“Yangfan”Project(ZYLX201802)。
文摘BACKGROUND:Acute pulmonary embolism(APE)with cardiac arrest(CA)is characterized by high mortality in emergency due to pulmonary arterial hypertension(PAH).This study aims to determine whether early pulmonary artery remodeling occurs in PAH caused by massive APE with CA and the protective effects of increasing angiotensin-converting enzyme(ACE)2-angiotensin(Ang)(1-7)-Mas receptor axis and ACE-Ang II-Ang II type 1 receptor(AT1)axis(ACE2/ACE axes)ratio on pulmonary artery lesion after return of spontaneous circulation(ROSC).METHODS:To establish a porcine massive APE with CA model,autologous thrombus was injected into the external jugular vein until mean arterial pressure dropped below 30 mmHg(1 mmHg=0.133 kPa).Cardiopulmonary resuscitation and thrombolysis were delivered to regain spontaneous circulation.Pigs were divided into four groups of five pigs each:control group,APE-CA group,ROSC-saline group,and ROSC-captopril group,to examine the endothelial pathological changes and expression of ACE2/ACE axes in pulmonary artery with or without captopril.RESULTS:Histological analysis of samples from the APE-CA and ROSC-saline groups showed that pulmonary arterioles were almost completely occluded by accumulated endothelial cells.Western blotting analysis revealed a decrease in the pulmonary arterial ACE2/ACE axes ratio and increases in angiopoietin-2/angiopoietin-1 ratio and expression of vascular endothelial growth factor(VEGF)in the APE-CA group compared with the control group.Captopril significantly suppressed the activation of angiopoietin-2/angiopoietin-1 and VEGF in plexiform lesions formed by proliferative endothelial cells after ROSC.Captopril also alleviated endothelial cell apoptosis by increasing the B-cell lymphoma-2(Bcl-2)/Bcl-2-associated X(Bax)ratio and decreasing cleaved caspase-3 expression.CONCLUSION:Increasing the ACE2/ACE axes ratio may ameliorate pulmonary arterial remodeling by inhibiting the apoptosis and proliferation of endothelial cells after ROSC induced by APE.
基金the National Natural Science Foundation of China,No.81000140,No.81770358,and No.82000339Natural Science Foundation of Hunan Province,No.2017JJ3486and the Fund for Health Care in Hunan Province,No.B2017-01.
文摘BACKGROUND The accumulation of advanced glycation end products(AGEs)have been implicated in the development and progression of diabetic vasculopathy.However,the role of profilin-1 as a multifunctional actin-binding protein in AGEs-induced atherosclerosis(AS)is largely unknown.AIM To explore the potential role of profilin-1 in the pathogenesis of AS induced by AGEs,particularly in relation to the Janus kinase 2(JAK2)and signal transducer and activator of transcription 3(STAT3)signaling pathway.METHODS Eighty-nine individuals undergoing coronary angiography were enrolled in the study.Plasma cytokine levels were detected using ELISA kits.Rat aortic vascular smooth muscle cells(RASMCs)were incubated with different compounds for different times.Cell proliferation was determined by performing the MTT assay and EdU staining.An AGEs-induced vascular remodeling model was established in rats and histological and immunohistochemical analyses were performed.The mRNA and protein levels were detected using real-time PCR and Western blot analysis,respectively.In vivo,shRNA transfection was performed to verify the role of profilin-1 in AGEs-induced proatherogenic mediator release and aortic remodeling.Statistical analyses were performed using SPSS 22.0 software.RESULTS Compared with the control group,plasma levels of profilin-1 and receptor for AGEs(RAGE)were significantly increased in patients with coronary artery disease,especially in those complicated with diabetes mellitus(P<0.01).The levels of profilin-1 were positively correlated with the levels of RAGE(P<0.01);additionally,the levels of both molecules were positively associated with the degree of coronary artery stenosis(P<0.01).In vivo,tail vein injections of AGEs induced the release of proatherogenic mediators,such as asymmetric dimethylarginine,intercellular adhesion molecule-1,and the N-terminus of procollagen III peptide,concomitant with apparent aortic morphological changes and significantly upregulated expression of the profilin-1 mRNA and protein in the thoracic aorta(P<0.05 or P<0.01).Downregulation of profilin-1 expression with an shRNA significantly attenuated AGEs-induced proatherogenic mediator release(P<0.05)and aortic remodeling.In vitro,incubation of vascular smooth muscle cells(VSMCs)with AGEs significantly promoted cell proliferation and upregulated the expression of the profilin-1 mRNA and protein(P<0.05).AGEs(200μg/mL,24 h)significantly upregulated the expression of the STAT3 mRNA and protein and JAK2 protein,which was blocked by a JAK2 inhibitor(T3042-1)and/or STAT3 inhibitor(T6308-1)(P<0.05).In addition,pretreatment with T3042-1 or T6308-1 significantly inhibited AGEs-induced RASMC proliferation(P<0.05).CONCLUSION AGEs induce proatherogenic events such as VSMC proliferation,proatherogenic mediator release,and vascular remodeling,changes that can be attenuated by silencing profilin-1 expression.These results suggest a crucial role for profilin-1 in AGEs-induced vasculopathy.
基金The project supported by National Natural Science Foundation of China(81273512,81460010)by Natural Science Foundation of Jiangxi province(20142BAB215035)
文摘OBJECTIVE To explore the role of calpain in in pulmonary vascular remodeling in hypoxia induced pulmonary hypertension and the underlying mechanism.METHODS Sprague-Dawley rats were randomly divided into hypoxia group and normoxia control group.Right ventricular systolic pressure(RVSP)and mean pulmonary artery pressure(m PAP)were monitored by the method of right external jugular vein cannula.Right ventricular hypertrophy index was expressed as the ratio of right ventricular weight to left ventricular weight(left ventricle plus septum weight).Level of calpain-1,calpain-2and calpain-4 m RNA in pulmonary artery trunk were determined by real-time PCR.Expression of calpain-1,calpain-2 and calpain-4 protein was determined by Western Blot.Primary rat pulmonary arterial smooth muscle cells(PASMCs)were divided into 4 groups:normoxia control group,normoxia+MDL28170 group,hypoxia group and hypoxia+MDL28170 group.Cell proliferation was detected by MTS and flow cytometry.Level of Ki-67 and PCNA m RNA were determined by real-time PCR.RESULTS RVSP,m PAP and right ventricular remodeling index were significantly higher in the hypoxia group than those in the normoxia group.In the hypoxia group,pulmonary vascular remodeling occurred,and the expression of calpain-1,calpain-2 and calpain-4 m RNA and protein expression was increased in the pulmonary artery.MDL28170 significantly inhibited hypoxia-induced proliferation of PASMCs accompanied with decreased Ki-67and PCNA m RNA expression.CONCLUSION Calpain mediated vascular remodeling via promoting proliferation of PASMCs in hypoxia induced pulmonary hypertension.
基金supported by Khon Kaen University under Grants(number 6100049 and 6200037),Thailand
文摘Objective:To evaluate the potential therapeutic effect of Sang-Yod rice bran hydrolysates(SRH)and in combination with lisinopril against hypertension,endothelial dysfunction,vascular remodeling,and oxidative stress in rats with nitric oxide deficiency-induced hypertension.Methods:Hypertension was induced in male Sprague-Dawley rats by administration of a nitric oxide synthase inhibitor,Nω-nitro-L-arginine methyl ester(L-NAME)in drinking water for 6 weeks.Hypertensive rats were administered daily with SRH(500 mg/kg/day),lisinopril(1 mg/kg/day),or the combination of SRH and lisinopril by gastric lavage for the last 3 weeks of L-NAME treatment.Hemodynamic status,vascular reactivity to vasoactive agents,and vascular remodeling were assessed.Blood and aortic tissues were collected for measurements of oxidative stress markers,plasma angiotensin-converting enzyme(ACE)activity,plasma angiotensinⅡ,and protein expression.Results:L-NAME induced remarkable hypertension and severe oxidative stress,and altered contents of smooth muscle cells,elastin,and collagen of the aortic wall.SRH or lisinopril alone reduced blood pressure,restored endothelial function,decreased plasma ACEs and angiotensinⅡlevels,alleviated oxidant markers and glutathione redox status,and restored the vascular structure.The effects were associated with increased expression of endothelial nitric oxide synthase and decreased expression of gp91phox and AT1R expression.The combination of SRH and lisinopril was more effective than monotherapy.Conclusions:SRH alone or in combination with lisinopril exert an antihypertensive effect and improve endothelial function and vascular remodeling through reducing oxidative stress and suppressing elevated renin-angiotensin system.
基金The project supported by National Natural Science Foundation of China(81102445 and81670456)Beijing Natural Science Foundation(7162132)the PUMC Youth Fund and the Fundamental Research Funds for the Central Universities(33320140069)
文摘Vascular remodeling,which can be found in atherosclerosis,restenosis after angioplasty,hypertension,and some other frequent and serious chronic diseases.Smooth muscle cell(SMC)phenotype change,which has been described as converting from a contractile state into a synthetic phenotype,is a crucial event during vascular remodeling.Recently,micro RNAs(mi RNAs)a kind of small non-coding RNA molecules,has been proven to target critical genes of cell signaling pathways to regulate SMC phenotypic change.By searching the Pub Med,Embase,reviews,and reference listsof relevant papers,we systematically carried out a review of the literature to provide an overview of the mi RNAs and their target genes in cell signaling pathways,focus inthe pathways involving in SMC phenotype change.To be specific,mi RNAs that regulate genes involved in the MAPK signaling pathways(such as:mi R-155,mi R-92a,mi R-424/503,mi R-133,mi R-181b,mi R-31,mi R-1298,mi R-132,mi R-200c and mi R-483-3p),mi RNAs target genes involved in the TGF-βsignaling pathways(including mi R-24,mi R-17/92 cluster,mi R-599,mi R-21 and mi R-143/145),mi RNAs target the genes involved in the AMPK signaling pathways including mi R-144/451 and mi R-195,mi RNAs target the genes involved in the PI3K-Akt signaling pathways(including mi R-138,mi R-34c,mi R-223,mi R-761,mi R-10a,mi R-146a),mi R-199a-5ptargets the genes involved in the Wnt signaling pathways mi RNAs(mi R-221/222,mi R-15b,mi R-24/29a,mi R-224)involved in the PDGF signaling pathways and some mi RNAs(mi R-638,mi R-328,mi R-365,mi R-663,mi R-29b,mi R-130,mi R-142-5p,mi R-424/322)which regulate SMC phenotype change by other corresponding targets were in detailed discussed in our review.Exploring the regulation of miR NAs in key cellsignaling pathways-mediatedvascular remodeling wil have momentous impact on identifying novel therapeutic targets for its associated disease.
基金supported by the National Natural Science Foundation of China (81774105)。
文摘Objective: To investigate the bioactive components of Sangqi Qingxuan formula(SQQX), predict the pharmacological targets, and explore the mechanism of hypertensive vascular remodeling(HVR).Methods: Network pharmacology was adopted to predict how SQQX acts in HVR. The effectiveness was assessed by blood pressure measurements and pathological morphology observation based on a spontaneously hypertensive rat model, while the mechanism of SQQX on HVR was validated by immunohistochemistry(IHC) and western blot(WB) according to the results of network pharmacology.Results: There were 130 bioactive components of SQQX and 231 drug targets predicted by the Traditional Chinese Medicine Systems Pharmacology Database. Subsequently, 181 common targets were identified for SQQX against HVR, with TP53, MAPK1, and AKT1 as the core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses was employed to identify the top 20 enriched functions and the top 20 pathways(P <.01). Finally, the key role of the ERK/MAPK signaling pathway in HVR was determined. The in vivo results suggested that SQQX reduced systolic blood pressure and increased the ratio of thoracic aortic wall thickness to lumen diameter. Additionally, compared with the model group, SQQX increased the expression of smooth muscle 22 alpha(IHC: P <.001;WB:P <.05) and decreased the expression of osteopontin(IHC: P <.001;WB: P <.05), ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), p-ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), and the ratio of pERK1/2 to ERK1/2 protein(IHC: P <.001).Conclusions: SQQX, which has multiple bioactive ingredients and potential targets, is an effective treatment for HVR. The mechanism of antihypertensive and vascular protection may be related to the inhibition of phenotypic transformation of vascular smooth muscle cells and the ERK/MAPK signaling pathway.
文摘Pathological vascular remodeling is characterized by thickening or thinning of the vessel wall through altering cellular and non-cellular components,which associates with various blood circulation disorders in brain,heart,lung,and peripheral vasculatures. Pathological vascular remodeling occurs in response to a variety of vascular insults such as mechanical(angioplasty or stenting) or biological(lipids,diabetes,smoking,or virus) injuries. It is a polygenic process involving multiple cell types in the vessel wall or circulation,including endothelial cells(ECs),smooth muscle cells(SMCs),fibroblasts,leukocytes,and platelets. One of hallmarks is the transition of vascular smooth muscle cells(SMCs)from a differentiated/quiescent contractile phenotype to a myofibroblast-like dedifferentiated/active so-called synthetic phenotype. Synthetic SMCs are proliferatory,migratory,secretory and inflammatory,playing key roles in the pathogenesis of vascular remodeling. In the normal vessel,ECs synthesize and secrete biological substances such as prostacyclins(PGI_2) and nitric oxide(NO) that not only function as vasodilators but also inhibit SMC phenotype transition and other properties associated with the synthetic phenotype. Cyclic nucleotides cAMP and cGMP are primary mediators of PGI_2 and NO,respectively,and play critical roles in control vascular structural integrity and function. Cyclic nucleotides are controlled by selective activation or inhibition of distinct cyclic nucleotide phosphodiesterase(PDE) isozymes catalyzing the degradation reaction. To date,more than 60 different PDE isoenzymes derived from 22 genes are identified and grouped into 11 broad families(PDE1-PDE11). PDEs are expressed in a cell/tissue-specific manner and only a few enzymes are expressed in any single cell type. Through systematic assessment of the expression levels of all known PDE isoforms in contractile versus synthetic SMCs,we found that the expression levels of a number of PDE are significantly altered between two SMC phenotypes. We then explored the functional roles and underlying mechanisms of these altered PDEs in vascular SMCs pathogenesis and vascular remodeling in vitro and in vivo using a variety of gain-of-or loss-of-function approaches. For example,we found that Ca^(2+)/calmodulinstimulated cAMP/cGMP-hydrolyzing PDE 1C is selectively expressed in synthetic SMCs in vitro and in various vascular disease models in vivo. PDE 1C upregulation contributes to a number of pathogenic functions of synthetic SMCs,such as cell proliferation,migration,and matrix protein metabolism.PDE 1C deficiency markedly attenuates intimal hyperplasia,atherosclerosis,and aortic aneurysm in experimental mouse disease models. These findings suggest that PDE 1C functions as a key regulator of the synthetic SMC pathology in vascular remodeling. Inhibiting PDE 1C function may represent a novel therapeutic strategy for protecting against the pathogenesis of vascular diseases.
文摘The current study revealed that increased synthesis and secretion of collagen types I and III play major roles in arterial wall remodeling, aneurysm formation, and atherosclerotic cap stability. The aim is to investigate the age-related changes of the procollagen alpha polypeptide gene mRNA and protein expression in the vascular smooth muscle cells (VSMCs) in rats, as well as the possible underlying mechanisms. We tested in vitro culture of VSMC from the thoracoabdominal aorta in neonate and 9-month-old healthy male Wistar rats;procollagen alpha polypeptide mRNA and procollagen alpha polypeptide protein expression were detected, using RT-PCR, VG staining, Western blot and ELISA methods. Semi-quantitative analysis displayed that, in the real-time reverse transcription polymerase chain reaction (RT-PCR), the type I collagen α polypeptide chain mRNA increased in the adult group, but not significantly (<em>P</em> = 0.05). Further, there was no significant difference between the two groups of type III collagen α polypeptide chain mRNA (<em>P</em> > 0.05). Both the type I and type III procollagen alpha polypeptide protein expression were increased significantly in the older group as compared with the young group (<em>P</em> < 0.05). This phenomenon mainly lies in the fact that the regulatory pathway on age-related changes of procollagen alpha polypeptides may be one of the molecular mechanisms in vascular remodeling during aging.
文摘Objective: To investigate the structural changes of aorta, and evaluate the effects of atorvastatinon the remodeling of thoracic aorta in spontaneously hypertensive rats(SHR) . Methods : Twelve eight-week-old SHR were randomized into atorvastatin treated group( ATV group, n = 6) and distilled water group( DW group, n = 6) ; Wistar-Kyoto rats(WKY) were used as normal controls. Atorvastatin was administered to ATV group for 10 weeks by gavage in mixture with distilled water( 1ml) ; the latter two groups were given the same amount of distilled water by gavage for 10 weeks. Systolic blood pressure of caudal artery was examined before and after treatment, and serum concentrations of total cholesterol, triglycerides and HDL-C were measured.Wall thickness, media thickness, medial cross-sectional area and lumen diameter of thoracic aorta were assessed with computed video processing. Results: Systolic blood pressure in ATV group was markedly lower than that in DW group( P < 0.01). Compared with DW group and WKY group, serum concentrations of total cholesterol, triglycerides and HDL-C in ATV group were significantly lower( P < 0.01, P < 0.05). Wall thickness, media thickness, and medial cross-sectional area to lumen ratio in DW group were significantly higher than those in WKY group and ATV group( P < 0.01, P < 0.05), but no such difference was found between WKY group and ATV group( P > 0.05 ). Conclusion : Vascular structural changes of aorta are due to the alteration of the vessel wall in early stage of SHR. Atorvastatin can markedly improve vascular remodeling.
文摘We investigated the expression of heme oxygenase 1 (HO 1) gene and production of endogenous carbon monoxide (CO) in the rat lung tissue at different time points of chronic hypoxic pulmonary hypertension and the effect of hemin on the expression of HO 1 gene and pulmonary hypertension. A rat model of hypoxic pulmonary hypertension was recreated by exposure to intermittent normobaric hypoxic environment (10 % O 2). Reverse transcriptase polymerase chain reaction (RT PCR) was performed to determine the level of HO 1 mRNA in the rat lung tissue and double wave length spectrophotometry was used to evaluate the quantity of COHb in arterial blood. Cardiac catheterization was employed to measure the right ventricular systolic pressure (RVSP) and HE staining was performed in dissected lung tissue to observe the pathological changes of the intra acinar pulmonary arteries (IAPA). It was found that (1) There was a low level of HO 1 mRNA in normal rat lung tissue, but the level of HO 1 mRNA increased by 2-4 times in the lung tissue of hypoxic rats ( P <0.01). The quantity of COHb was 2-3 times those of control group ( P <0.01 or P <0.05). These were accompanied by the increased of RVSP and the thickened IAPA; (2) Hemin could keep the HO 1 mRNA and COHb in the hypoxic rat lung tissue at a high level, and partially suppressed the increase of rat RVSP, thereby ameliorating the pathological changes of IAPA. In conclusion, the upregulation of the expression of HO 1 gene and production of CO in the rat lung of hypoxic pulmonary hypertension plays a role of inhibition in the development of hypoxic pulmonary hypertension. Hemin has a therapeutic effect on hypoxic pulmonary hypertension.
基金Supported by Comisión Nacional de Investigación Científicay Tecnológica(CONICYT,Chile)grants FONDECYT 1121060(to JEJ and MPO),FONDEF D11I1122(to MPO and JEJ)and FONDAP 15130011(to MPO)
文摘Asymptomatic organ damage due to progressive kidney damage, cardiac hypertrophy and remodeling put hypertensive patients at high risk for developing heart and renal failure, myocardial infarction and stroke. Current antihypertensive treatment normalizes high blood pressure, partially reverses organ damage, and reduces the incidence of heart and renal failure. Activation of the renin-angiotensin system(RAS) is a primary mechanism of progressive organ damage and, specifically, a major cause of both renal and cardiovascular fibrosis. Currently, inhibition of the RAS system [mainly with angiotensin I converting enzyme inhibitors or angiotensin II(Ang II) receptor antagonists] is the most effective antihypertensive strategy for normalizing blood pressure and preventing target organ damage. However, residual organ damage and consequently high risk for cardiovascular events and renal failure still persist. Accordingly, in hypertension, it is relevant to develop new therapeutic perspectives, beyond reducing blood pressure to further prevent/reduce target organ damage by acting on pathways that trigger and maintain cardiovascular and renal remodeling. We review here relevant novel mechanisms of target organ damage in hypertension, their role and evidence in prevention/regression of cardiovascular remodeling and their possible clinical impact as well. Specifically, we focus on the signaling pathway Rho A/Rho kinase, on the impact of the vasodilatory peptides from the RAS and some insights on the role of estrogens and myocardial chymase in cardiovascular hypertensive remodeling.
基金supported by grants from the National Natural Science Foundation of China (31101733)
文摘The objective of this study was to evaluate the effects of low ambient temperature(LAT) and dietary vitamin C(VC)supplementation on pulmonary vascular remodeling(PVR) and the relative expression of hypoxia inducible factor-1α(HIF-1α),vascular endothelial growth factor(VEGF) and its receptor 2(VEGFR-2) mRNA of lungs in 21-d-old broilers.4001-d-old male Cobb broilers were assigned randomly to 4 treatments as follows for 21 d:1) LAT and a basal diet;2) LAT and a basal diet supplemented with 1 000 mg kg^(-1) VC(LAT+VC);3) normal ambient temperature(NAT) and a basal diet;4) NAT and a basal diet supplemented with 1 000 mg kg^(-1) VC(NAT+VC).Each treatment was composed of 10 replicates of 10 birds per replicate.Samples of lung were collected after the broilers were killed at d 21.LAT increased the ratio of vessel wall area to vessel total area(WA/TA,%) and mean media thickness in pulmonary arterioles(mMTPA,%)(P<0.05).Dietary VC supplementation decreased mMTPA(P<0.05),but had no effect on the WA/TA.LAT increased(P<0.05) the relative mRNA expression of HIF-1α,VEGF and VEGFR-2,while adding VC to the diet could decrease(P<0.05) their relative mRNA expression.A significant positive correlation existed between the level of VEGF mRNA expression and the value of WA/WT(P<0.05) or mMTPA(P<0.05).These results suggested LAT resulted in pulmonary vascular remodeling,and the increase of HIF-1a,VEGF and VEGFR-2 mRNA expression,and dietary VC supplementation can alleviate pulmonary vascular remodeling in broiler by affecting these gene expression.
基金supported by grants from the National Natural Science Foundation of China ( 11625209,11572199,31670958)
文摘Vascular remodeling is the essential pathogenic process of various cardiovascular disorders,including hypertension,atherosclerosis,stroke,and restenosis after vein graft.The main characterization of vascular remodeling is abnormal variations of vascular cell phenotype,morphological structure and functions such as migration,hypertrophy,proliferation and apoptosis.Numerous researches revealed that mechanical stress,including shear stress and cyclic stretch,participates in physiological vascular homeostasis,or pathophysiological vascular remodeling.The understanding of mechanobiological mechanism in vascular remodeling will play a unique role in understanding human physiology and disease,and will generate important theoretical and clinical significance [2].Non-coding RNAs are newly recognized RNAs which cannot be translated into proteins but are involved in epigenetic modification of gene regulation.The studies revealed that non-coding RNAs,such as microRNAs(miRNAs)and long noncoding RNAs(long ncRNAs,IncRNA),as well as small interfering RNAs(siRNAs),piwi-interacting RNAs(piRNAs),small nucleolar RNAs(snoRNAs),play essential roles in the regulation of various processes,such as metabolism,development,cell proliferation,cell apoptosis,cell differentiation,oncogenesis and vascular homeostasis[5].However,the roles of non-coding RNAs in the cardiovascular system under mechanical stresses are still not clarified.Our recent researches detected the mechanical regulation of IncRNAs and miRNAs in vascular remodeling.LncRNAs are non-protein-coding transcripts that are longer than 200 nucleotides(nt),which is an arbitrary cut-off value that distinguishes these transcripts from other small RNAs.Unlike the well-established mechanism of microRNA action,the functional mode of IncRNAs is not fully understood.Increasing evidence shows that IncRNAs modulate gene expression via a multilevel-regulated pathway.Given their large number and complicated functional modes,lncRNAs are emerging as important regulators of a variety of cellular responses,developmental processes and diseases.Using a gene microarray,we screened the differences in the IncRNAs and mRNAs between spontaneously hypertensive rats(SHR)and Wistar Kyoto rats(WKY).The results showed that 68 IncRNAs and 255 mRNAs were up-regulated in the aorta of SHR,while 167 IncRNAs and 272 mRNAs were down-regulated.Expressions of the screened IncRNAs,including XR007793,were validated by real-time PCR.A co-expression network was composed,and gene function was analysed using Ingenuity Pathway Analysis.In vitro,vascular smooth muscle cells(VSMCs)were subjected to cyclic stretch at a magnitude of 5%(physiological normotensive cyclic stretch)or 15%(pathological hypertensive cyclic stretch)by Flexercell-5000TM.15%-cyclic-stretch increased XR007793 expression.XR007793 knockdown attenuated VSMC proliferation and migration and inhibited co-expressed genes such as signal transducers and activators of transcription 2(stat2),LIM domain only 2(lmo2)and interferon regulatory factor 7(irf7)[4].Illuminating the role of IncRNAs in vascular remodeling induced by hyper mechanical stretch may provide deeper insight into the mechanobiological mechanism underlying hypertension,and contribute to identifying potential targets for hypertension therapy.miRNAs are endogenous,non-coding,single-stranded RNAs of 18-22 nucleotides that constitute a novel class of gene regulators.miRNAs bind to their target genes within their 3’-untranslated regions(3’-UTRs),leading to direct degradation of mRNA or translational repression by a complete,i.e.in plants,or incomplete,i.e.in animals,complement respectively.Our resent works revealed several important mechano-responsive miRNA and their potential effects in vascular remodeling.Forexample,miRNA-33 is regulated by cyclic stretch in the grafted vessels,which targets to BMP3 and subsequent modulates smad signaling pathway.The miRNA-33-BMP3-smad pathway protects against venous VSMC proliferation in response to arterial cyclic stretch.Therefore,miRNA-33 may be a potential therapeutic target in autologous vein grafted surgery,and locally overexpression of miR-33 may attenuates neointimal hyperplasia of grafted human saphenous vein [3].The unpublished data revealed that 15%cyclic stretch also significantly elevated the expression of miRNA-124-3p which bound to the 3’UTR of Lmna mRNA,and then negatively regulated protein expression of lamin A/C which is the important skeletal proteins in nucleus.In addition to primary intracellular locations of miRNAs,our recent study showed that miRNAs can be secreted and protected extracellularly via inclusion into membrane-derived vesicles including microparticles.Microparticles are extracellular vesicles ranging from 0.1 to 1μm in size and have been shown to deliver various bioactive molecules,i.e.,chemokines,enzymes and miRNAs,to recipient cells.Increasing evidence shows that microparticles play a pivotal role in many pathological processes,such as cancer,inflammatory diseases and cardiovascular disease.Our present study showed that platelet-derived microparticles(PMPs),which are released by active platelets,are important vehicles for communication and play crucial roles in inducing abnormal EC proliferation in hypertension.In briefly,EC proliferation was increased in renal hypertensive rats established by abdominal aortic coarctation compared to control rats and that elevated thrombin in plasma promoted platelet activation,which may induce the release of PMPs.miRNA array and qPCR revealed a higher level of miRNA-142-3p in platelets and PMPs.In vitro,PMPs delivered miRNA-142-3p into ECs and enhanced EC proliferation via Bcl-2-associated transcription factor 1(BCLAF1)and its downstream genes.These results indicated that PMPs deliver miRNA-142-3p from activated platelets into ECs and that miRNA-142-3p may play important roles in EC dysfunction under hypertensive conditions and might be a novel therapeutic target for maintaining EC homeostasis in hypertension[1].These results provide possible mechanisms by which non-coding RNAs regulate cellular functions under different mechanical stresses,and suggest a novel potential therapeutic approach for vascular remodeling.The further studies on noncoding RNAs may provide new insight into understanding the mechanism of vascular remodeling in different various cardiovascular disorders,and may provide novel targets for the maintenance of vascular homeostasis.
文摘Intravenous and intratracheal implantation of mesenchymal stem cells (MSCs) may offer ameliorating effects on pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats. The aim of this study was to examine the anti-remodeling effect of intravenous MSCs (VMSCs) and intratracheal MSCs (TMSCs) in rats with PH, and the underlying mechanisms. MSCs were isolated from rat bone marrow and cultured. PH was induced in rats by intraperitoneal injection of MCT. One week after MCT administration, the rats were divided into 3 groups in terms of different treatments: VMSCs group (intravenous injection of MSCs), TMSCs group (intratracheal injection of MSCs), PH group (no treatment given). Those receiving saline instead of MCT served as negative control (control group). Pulmonary arterial structure was pathologically observed, pulmonary arterial dynamics measured, and remodeling-associated cytokines Smad2 and Smad3 detected in the lungs, three weeks after MCT injection. The results showed that PH group versus control group had higher pulmonary arterial pressure (PAP) and wall thickness index (WTI) 21 days after MCT treatment. The expression of phosphorylated (p)-Smad2 and the ratio of p-Smad2/Smad2 were much higher in PH group than in control group. Fluorescence-labeled MSCs were extensively distributed in rats' lungs in VMSCs and TMSCs groups 3 and 14 days after transplantation, but not found in the media of the pulmonary artery. WTI and PAP were significantly lower in both VMSCs and TMSCs groups than in PH group three weeks after MCT injection. The p-Smad2 expression and the ratio of p-Smad2/Smad2 were obviously reduced in VMSCs and TMSCs groups as compared with those in PH group. In conclusion, both intravenous and intratracheal transplantation of MSCs can attenuate PAP and pulmonary artery remodeling in MCT-induced PH rats, which may be associated with the early suppression of Smad2 phosphorylation via paracrine pathways.
基金supported by the National Natural Science Foundation of China (No. 81070044)
文摘This study investigated the potential role of ERK1/2-cyclinE1 signaling pathway in rat pulmonary artery smooth muscle cells (rPASMCs) proliferation and pulmonary vascular remodeling induced by cigarette smoke exposure. A total of 24 male Wistar rats were randomly divided into 4 groups: control group (C group), S-1M, S-3M and S-6M groups (animals in the groups were exposed to smoke for 1, 3, and 6 months, respectively). HE staining and anti-α-smooth muscle actin antibody staining were performed to observe the degree of pulmonary vascular remodeling. Immunohistochemis- try and Western blotting were performed to evaluate ERK1/2 and cyclinE1 expression in pulmonary vessels. Primary cultured rat pulmonary artery smooth muscle cells (rPASMCs) were exposed to ciga- rette smoke extract (CSE). ERK inhibitor (PD98059) and cyclinE1 siRNA were used to verify the role of ERK1/2 and cyclinE1 in CSE-induced rPASMCs proliferation. Cell proliferation was assessed by cell counting and 5-bromo-2-deoxyuridine (BrdU) incorporation. Our results showed that abnormal pulmo- nary vascular remodeling was found in cigarette smoked rats. Compared to C group, activated ERK1/2 and cyclinE1 expression was significantly increased in smoke-exposure groups. This up-regulated ex- pression was positively correlated with the severity of pulmonary vascular remodeling, and there was positive correlation between the expression of ERK1/2 and cyclinE1. PD98059 and cyclinE1 siRNA in- hibited the proliferation of rPASMCs. The expression of cyclinE1 could be down-regulated by PD98059. Our data demonstrated that increased expression of ERK1/2 and cyclinE1 might be involved in the pathogenesis of abnormal rPASMCs proliferation and rat pulmonary vascular remodelling induced by cigarette smoke exposure.
基金Natural Science Foundation of China(81573645,81603101)the National Science and Technology Major Project(2013ZX09103001-008)
文摘OBJECTIVE The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling,which is characteristic of pulmonary arterial hypertension(PAH).In this study we exam-ined whether salvianolic acid A(SAA)extracted from the traditional Chinese medicine′Dan Shen′attenuated vascular remodeling in a PAH rat model,and elucidated the underlying mechanisms.METHODS PAH was induced in rats by injecting a single dose of monocrotaline(MCT 60 mg·kg-1,sc).The rats were orally treated with either SAA(0.3,1,3 mg·kg-1·d-1)or a positive control bosentan(30 mg·kg-1·d-1)for 4 weeks.Echocardiography and hemodynamic measurements were performed on d 28.Then the hearts and lungs were harvested,the organ indices and pulmonary artery wall thickness were calculated,and biochemical and histochemical analysis were conducted.The levels of apoptotic and signaling proteins in the lungs were measured using immunoblotting.RESULTS Treatment with SAA or bosentan effectively ameliorated MCTinduced pulmonary artery remodeling,pulmonary hemodynamic abnormalities and the subsequent increases of right ventricular systolic pressure(RVSP).Furthermore,the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium,parenchymal injury and collagen deposition in the lungs.Moreover,the treatments attenuated MCT-induced apoptosis and fibrosis in the lungs.The treatments partially restored MCT-induced reductions of bone morphogenetic protein typeⅡreceptor(BMPRⅡ)and phosphorylated Smad1/5 in the lungs.CONCLUSION SAA ameliorates the pulmonary arterial remodeling in MCT-induced PAH rats most likely via activating the BMPRⅡ-Smad pathway and inhibiting apoptosis.Thus,SAA may have therapeutic potential for the patients at high risk of PAH.
基金a grant from the National Natural Sciences Foundation of China (No. 30470759)
文摘In order to investigate the effects of puerarin on pulmonary vascular remodeling and protein kinase C-α (PKC-α) in chronic exposure smoke rats, 54 male Wistar rats were randomly di-vided into 7 groups: control group (C group), smoke exposure groups (S4w group, S8w group), puer-arin groups (P4w group, P8w group), propylene glycol control groups (PC4w group, PC8w group). Rats were exposed to cigarette smoke or air for 4 to 8 weeks. Rats in puerarin groups also received puer-arin. To evaluate vascular remodeling, alpha-smooth muscle actin (α-SM-actin) staining was used to count the percentage of completely muscularised vessels to intraacinar pulmonary arteries (CMA/IAPA) which was determined by morphometric analysis of histological sections. Pulmonary artery smooth muscle cell (PASMC) apoptosis was detected by in situ end labeling technique (TUNEL), and proliferation by proliferating cell nuclear antigen (PCNA) staining. Reverse transcrip-tion-polymerase chain reaction (RT-PCR), immunofluorescence staining and Western blot analysis were done to detect the PKC-α mRNA and protein expression in pulmonary arteries. The results showed that in cigarette smoke-exposed rats the percentage of CMA/IAPA and α-SM-actin expres-sion were increased greatly, PASMC apoptosis was increased and proliferation was markedly in-creased; Apoptosis indices (AI) and proliferation indices (PI) were higher than in C group; AI and PI were correlated with vascular remodeling indices; The expression of PKC-α mRNA and protein in pulmonary arteries was significantly higher than in C group. In rats treated with puerarin, the per-centage of CMA/IAPA and cell proliferation was reduced, whereas PASMC apoptosis was increased; The expression levels of PKC-α mRNA and protein were lower than in smoke exposure rats. There was no difference among all these data between S groups and PC groups. These findings suggested that cigarette smoke-induced pulmonary vascular remodeling was most likely an effect of the imbal-ance of PASMC proliferation and apoptosis. Puerarin appears to be able to reduce cell proliferation and vascular remodeling possibly through PKC signaling transduction pathway.
文摘Objective: To study the effects of serum Fractalkine on vascular remodeling and oxidative stress activation in patients with COPD complicated by pulmonary heart disease. Methods:Patients who were hospitalized in Chongqing Armed Corps Police Hospital due to COPD between June 2014 and April 2017 were selected, the patients with COPD alone were included in COPD group, and the patients with COPD complicated by pulmonary heart disease were included in COPD+PHD group;healthy volunteers who underwent physical examination during the same period were selected as the control group of the study. The serum was collected to determine the contents of Fractalkine, vascular remodeling indexes and oxidative stress indexes. Results: Serum Fractalkine, ANG-2, MMP2, MMP9, VEGF, FGF2, Nogo-B, ET-1 and MDA contents of COPD+PHD group and COPD group were higher than those of control group whereas T-AOC contents were lower than that of control group;serum Fractalkine, ANG-2, MMP2, MMP9, VEGF, FGF2, Nogo-B, ET-1 and MDA contents of COPD+PHD group were higher than those of COPD group whereas T-AOC content was lower than that of COPD group. Serum ANG-2, MMP2, MMP9, VEGF, FGF2, Nogo-B, ET-1 and MDA contents of COPD+PHD group of patients with high Fractalkine content were significantly higher than those of COPD+PHD group of patients with low Fractalkine content whereas T-AOC content was lower than that of COPD+PHD group of patients with low Fractalkine content. Conclusion: The increase of serum Fractalkine in patients with COPD complicated by pulmonary heart disease can aggravate the vascular remodeling and promote the oxidative stress activation.
