Objective Endothelial dysfunction is one candidate for triggering neointima formation after arteriovenous grafts(AVGs),but the factors mediating this process are unclear.The purpose of this study was to investigate th...Objective Endothelial dysfunction is one candidate for triggering neointima formation after arteriovenous grafts(AVGs),but the factors mediating this process are unclear.The purpose of this study was to investigate the role of endoplasmic reticulum stress(ERS)-induced endothelial dysfunction in neointima formation following AVGs in high-fat diet(HFD)mice.Methods CCAAT-enhancer-binding protein-homologous protein(CHOP)knockout(KO)mice were created.Mice were fed with HFD to produce HFD model.AVGs model were applied in the groups of WT ND,WT HFD,and CHOP KO HFD.Human umbilical vein endothelial cells(HUVECs)were cultured with oxidized low density lipoprotein(ox-LDL)(40 mg/L)for the indicated time lengths(0,6,12,24 h).ERS inhibitor tauroursodeoxycholic acid(TUDCA)was used to block ERS.Immunohistochemical staining was used to observe the changes of ICAM1.Changes of ERS were detected by real-time RT-PCR.Protein expression levels and ERS activation were detected by Western blotting.Endothellial cell function was determined by endothelial permeability assay and transendothelial migration assay.Results HFD increased neointima formation in AVGs associated with endothelial dysfunction.At the same time,ERS was increased in endothelial cells(ECs)after AVGs in mice consuming the HFD.In vitro,ox-LDL was found to stimulate ERS,increase the permeability of the EC monolayer,and cause endothelial dysfunction.Blocking ERS with TUDCA or CHOP siRNA reversed the EC dysfunction caused by ox-LDL.In vivo,knockout of CHOP(CHOP KO)protected the function of ECs and decreased neointima formation after AVGs in HFD mice.Conclusion Inhibiting ERS in ECs could improve the function of AVGs.展开更多
Ischemic stroke occurs under a variety of clinical conditions and has different pathogeneses,resulting in necrosis of brain parenchyma.Stroke pathogenesis is characterized by neuroinflammation and endothelial dysfunct...Ischemic stroke occurs under a variety of clinical conditions and has different pathogeneses,resulting in necrosis of brain parenchyma.Stroke pathogenesis is characterized by neuroinflammation and endothelial dysfunction.Some of the main processes triggered in the early stages of ischemic damage are the rapid activation of resident inflammatory cells(microglia,astrocytes and endothelial cells),inflammatory cytokines,and translocation of intercellular nuclear factors.Inflammation in stroke includes all the processes mentioned above,and it consists of either protective or detrimental effects concerning the“polarization”of these processes.This polarization comes out from the interaction of all the molecular pathways that regulate genome expression:the epigenetic factors.In recent years,new regulation mechanisms have been cleared,and these include non-coding RNAs,adenosine receptors,and the activity of mesenchymal stem/stromal cells and microglia.We reviewed how long non-coding RNA and microRNA have emerged as an essential mediator of some neurological diseases.We also clarified that their roles in cerebral ischemic injury may provide novel targets for the treatment of ischemic stroke.To date,we do not have adequate tools to control pathophysiological processes associated with stroke.Our goal is to review the role of non-coding RNAs and innate immune cells(such as microglia and mesenchymal stem/stromal cells)and the possible therapeutic effects of their modulation in patients with acute ischemic stroke.A better understanding of the mechanisms that influence the“polarization”of the inflammatory response after the acute event seems to be the way to change the natural history of the disease.展开更多
Objective To explore the relationship of inflammation and endothelial dysfunction with risks to cardiovascular disease （CVD）. Methods Blood pressure, body weight, body height, waist circumference and lifestyle risk ...Objective To explore the relationship of inflammation and endothelial dysfunction with risks to cardiovascular disease （CVD）. Methods Blood pressure, body weight, body height, waist circumference and lifestyle risk factors were measured and studied among 2589 participants in Inner Mongolia of China, and biomarkers of inflammation and endothelial dysfunction including high-sensitivity C-reactive protein （hsCRP）, soluble inter-cellular adhesion molecule-1 （slCAM-1）, soluble E-selectin （sE-selectin）, and angiotensin II were investigated. Results Subjects with metabolic risk factors for CVD had higher levels of hsCRP, sE-selectin and slCAM-1 than those without such risk factors （all P〈O.05）. Levels of all biomarkers positively and significantly increased with aggregation of the metabolic risk factors among the subjects （all P for trend 〈0.001）. Data from the multivariate analysis showed that participants with high levels of hsCRP [odds ratio （OR}： 1.96, 95% confidence interval （CI）： 1.52-2.53], sE-selectin （OR： 1.35, 95% Cl： 1.05-1.72）, and angiotensin II （OR： 1.81, 95% CI＂ 1.40-2.33） were more likely to develop hypertension; participants with high levels of hsCRP （OR： 2.33, 95% CI： 1.85-2.94）, sE-selectin （OR： 1.24, 95% CI： 1.00-1.54）, and slCAM-1 （OR： 1.70, 95% CI： 1.30-2.22） were more likely to develop dyslipidemia, and those with high levels of hsCRP （OR： 2.95, 95% CI： 2.27-3.83） and slCAM-I（OR： 2.80, 95% CI： 2.06-3.80） were more likely to develop hyperglycemia. Conclusion Biomarkers of inflammation and endothelial dysfunction were separately associated with relevant metabolic risk factors for CVD. And appropriate measures should be taken to control inflammation and improve endothelial function among individuals with different metabolic risk factors for CVD.展开更多
BACKGROUND Endothelial dysfunction,a hallmark of diabetes,is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications.However,the underlying mechanisms are still not fully und...BACKGROUND Endothelial dysfunction,a hallmark of diabetes,is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications.However,the underlying mechanisms are still not fully understood.Ferroptosis is a newly defined regulated cell death driven by cellular metabolism and irondependent lipid peroxidation.Although the involvement of ferroptosis in disease pathogenesis has been shown in cancers and degenerative diseases,the participation of ferroptosis in the pathogenesis of diabetic endothelial dysfunction remains unclear.AIM To examine the role of ferroptosis in diabetes-induced endothelial dysfunction and the underlying mechanisms.METHODS Human umbilical vein endothelial cells(HUVECs)were treated with high glucose(HG),interleukin-1β(IL-1β),and ferroptosis inhibitor,and then the cell viability,reactive oxygen species(ROS),and ferroptosis-related marker protein were tested.To further determine whether the p53-xCT(the substrate-specific subunit of system Xc-)-glutathione(GSH)axis is involved in HG and IL-1βinduced ferroptosis,HUVECs were transiently transfected with p53 small interfering ribonucleic acid or NC small interfering ribonucleic acid and then treated with HG and IL-1β.Cell viability,ROS,and ferroptosis-related marker protein were then assessed.In addition,we detected the xCT and p53 expression in the aorta of db/db mice.RESULTS It was found that HG and IL-1βinduced ferroptosis in HUVECs,as evidenced by the protective effect of the ferroptosis inhibitors,Deferoxamine and ferrostatin-1,resulting in increased lipid ROS and decreased cell viability.Mechanistically,activation of the p53-xCT-GSH axis induced by HG and IL-1βenhanced ferroptosis in HUVECs.In addition,a decrease in xCT and the presence of deendothelialized areas were observed in the aortic endothelium of db/db mice.CONCLUSION Ferroptosis is involved in endothelial dysfunction and p53-xCT-GSH axis activation plays a crucial role in endothelial cell ferroptosis and endothelial dysfunction.展开更多
Microparticles are small cell vesicles that can be released by almost all eukaryotic cells during cellular stress and cell activation. Within the last 1-2 decades it has been shown that microparticles are useful blood...Microparticles are small cell vesicles that can be released by almost all eukaryotic cells during cellular stress and cell activation. Within the last 1-2 decades it has been shown that microparticles are useful blood surrogate markers for different pathological conditions, such as vascular inflammation, coagulation and tumour diseases. Several studies have investigated the abundance of microparticles of different cellular origins in multiple cardiovascular diseases. It thereby has been shown that microparticles released by platelets, leukocytes and endothelial cells can be found in conditions of endothelial dysfunction, acute and chronic vascular inflammation and hypercoagulation. In addition to their function as surrogate markers, several studies indicate that circulating microparticles can fuse with distinct target cells, such as endothelial cells or leukocyte, and thereby deliver cellular components of their parental cells to the target cells. Hence, microparticles are a novel entity of circulating, paracrine, biological vectors which can influence the phenotype, the function and presumably even the transcriptome of their target cells.This review article aims to give a brief overview about the microparticle biology with a focus on endothelial activation and arterial hypertension. More detailed information about the role of microparticles in pathophysiology and disease can be found in already published work.展开更多
Metabolic syndrome is a cluster of several clinical conditions characterized by insulin-resistance and high cardiovascular risk. Non-alcoholic fatty liver disease is the liver expression of the metabolic syndrome, and...Metabolic syndrome is a cluster of several clinical conditions characterized by insulin-resistance and high cardiovascular risk. Non-alcoholic fatty liver disease is the liver expression of the metabolic syndrome, and insulin resistance can be a frequent comorbidity in several chronic liver diseases, in particular hepatitis C virus infection and/or cirrhosis. Several studies have demonstrated that insulin action is not only relevant for glucose control, but also for vascular homeostasis. Insulin regulates nitric oxide production, which mediates to a large degree the vasodilating, antiinflammatory and antithrombotic properties of a healthy endothelium, guaranteeing organ perfusion. The effects of insulin on the liver microvasculature and the effects of IR on sinusoidal endothelial cells have been studied in animal models of non-alcoholic fatty liver disease. The hypotheses derived from these studies and the potential translation of these results into humans are critically discussed in this review.展开更多
Postprandial hyperglycemia has been reported to elicit endothelial dysfunction and provoke future cardiovascular complications. A reduction of postprandial blood glucose levels by the glucosidase inhibitor Fuscoporia ...Postprandial hyperglycemia has been reported to elicit endothelial dysfunction and provoke future cardiovascular complications. A reduction of postprandial blood glucose levels by the glucosidase inhibitor Fuscoporia obliqua was associated with a risk reduction of cardiovascular complications, but the effects of Fuscoporia obliqua on endothelial function have never been elucidated. This study is aimed to assess the efficacy of Fuscoporia obliqua on postprandial metabolic parameters and endothelial function in type 2 diabetic patients. Postprandial peak glucose (14.47±1.27 vs. 8.50±0.53 mmol/liter), plasma glucose excursion (PPGE), and change in the area under the curve (AUC) glucose after a single loading of test meal (total 450 kcal; protein 15.3%; fat 32.3%; carbohydrate 51.4%) were significantly higher in the diet-treated type 2 diabetic patients (n=14) than the age-and sex-matched controls (n=12). The peak forearm blood flow response and total reactive hyperemic flow (flow debt repayment) during reactive hyperemia, indices of resistance artery endothelial function on strain-gauge plethysmography, were unchanged before and after meal loading in the controls. But those of the diabetics were significantly decreased 120 and 240 min after the test meal. A prior administration of Fuscoporia obliqua decreased postprandial peak glucose, PPGE, and AUC glucose. The peak forearm blood flow and flow debt repayment were inversely well correlated with peak glucose, PPGE, and AUC glucose, but not with AUC insulin or the other lipid parameters. Even a single loading of the test meal was shown to impair the endothelial function in type 2 diabetic patients, and the postprandial endothelial dysfunction was improved by a prior use of Fuscoporia obliqua. Fuscoporia obliqua might reduce macrovascular complication by avoiding endothelial injury in postprandial hyperglycemic status.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
OBJECTIVE The Ca2+-activated Cl-channel(Ca CC)plays a crucial role in various physiological functions.Recent evidences suggest TMEM16A encodes CaC C in various cells,including endothelial cells.However,the role of TME...OBJECTIVE The Ca2+-activated Cl-channel(Ca CC)plays a crucial role in various physiological functions.Recent evidences suggest TMEM16A encodes CaC C in various cells,including endothelial cells.However,the role of TMEM16A in the vascular endothelial dysfunction in hypertension is unclear.METHODS In the study,RT-PCR,Western blotting,co-immunopricipitation,confocal imaging,patch-clamp,and endothelial-specific TMEM16A transgenic and knockout mice were employed.RESULTS We found that TMEM16A was expressed abundantly and functioned as Ca CC in endothelial cells.AngiotensinⅡ(AngⅡ)induced endothelial dysfunction with an increase in TMEM16A expression,which was alleviated by TMEM16A inhibitor.Further studies revealed that TMEM16A endothelial-specific knockout significantly lowered the blood pressure and ameliorated endothelial dysfunction in AngⅡ-induced hypertension,whereas,TMEM16A endothelial-specific overexpression showed the opposite effects.These results were related to the increased reactive oxygen species(ROS)generation,NADPH oxidase activation,and Nox2,p22phox expression facilitated by TMEM16A upon AngⅡ-induced hypertensive challenges.Moreover,TMEM16A directly interacted with Nox2 monomer and reduced the degradation of Nox2 through the proteasome-dependent endoplasmic recticulum-associated degradation pathway.TMEM16A also potentiated the translocation of p47phox and p67phox from cytosol to cell membrane and the subsequent interaction with Nox2.CONCLUSION Our results demonstrated that TMEM16A,as Ca CC,is a positive regulator of ROS generation via upregulating the activation of Nox2 NADPH oxidase in the vascular endothelium,and therefore facilitates endothelial dysfunction and hypertension.Modification of TMEM16A may be a novel therapeutic strategy for endothelial dysfunction-associated cardiovascular diseases.展开更多
Vascular remodeling is an adaptive response to various stimuli,including mechanical forces,inflammatory cy tokines and hormones.In the present study,we investigated the role of angiotensinII type 1 receptor(ATIR)and c...Vascular remodeling is an adaptive response to various stimuli,including mechanical forces,inflammatory cy tokines and hormones.In the present study,we investigated the role of angiotensinII type 1 receptor(ATIR)and calcium channel in carotid artery remodeling in response to increased biomechanical forces by using the transverse aortic constriction(TAC)rat model.TAC was induced on ten week-old male Sprague Dawley rats and these models were treated with ATIR blocker olmesartan(1 mg/kg/day)or/and calcium channel blocker(CCB)amlodipine(0.5 mgkgday)for 14 days.After the treatment,the right common carotid artery proximal to the band(RCCA-B)was collected for further assay.Results showed that olmesartan,but not amlodipine,significantly prevented TAC-induced adventitial hyperplasia.Similarly,olmesartan,but not amlodipine,significantly prevented vascular inflammation,as indicated by increased tumor necrosis factor a(TNF-a)and increased p65 phosphorylation,an indicator of nuclear factor K-light-chain-enhancer of activated B cells(NFkB)activation in RCCA-B.In contrast,both olmesartan and amlodipine reversed the decreased expression of endothelial nitric oxidase synthase(eNOS)and improved endothelium-dependent vasodilation,whereas combination of olmesartan and amlodipine showed no further synergistic protective effects.These results suggest that AT1R was involved in vascular remodeling and inflammation in response to pressure overload,whereas ATIR and subsequent calcium channel were involved in endothelial dysfunction.展开更多
Background Endothelial dysfunction is the initial stage in atherosclerotic formation and progression and is associated with high serum uric acid(SUA)level.We hypothesized that reactive hyperemia index(RHI),which refle...Background Endothelial dysfunction is the initial stage in atherosclerotic formation and progression and is associated with high serum uric acid(SUA)level.We hypothesized that reactive hyperemia index(RHI),which reflects endothelial function,is associated with SUA levels in elderly individuals with untreated mild hypertension.Methods We recruited 123 patients≥60 years with untreated mild hypertension.The association between SUA level and RHI was analyzed using univariate correlation analysis and multiple regression analysis.The receiver operating characteristic(ROC)curve was performed to validate the cutoff value of SUA that can be used to predict endothelial dysfunction.Results The serum uric acid level significantly increased in the RHI<1.67 group,and this result was still observed in the subgroup of men.RHI was inversely associated with SUA level(P=0.006)and the association was still observed after adjusting for factors,such as age,sex,smoking status,and creatinine level(P=0.014).In the subgroup analysis,a positive association was observed only in men.In the ROC curve analysis,the optimal cutoff values of SUA for predicting endothelial dysfunction was 293.5μmol/L in elderly mild hypertension patients and 287.0μmol/L in men.Conclusion A high SUA level was considered an independent predictor of endothelial dysfunction among elderly individuals,particularly men with untreated mild hypertension.展开更多
Endothelial dysfunction is implicated in a variety of cardiovascular diseases although the detailed mechanisms are not yet completely understood. A relationship has been suggested to exist between inflammation and end...Endothelial dysfunction is implicated in a variety of cardiovascular diseases although the detailed mechanisms are not yet completely understood. A relationship has been suggested to exist between inflammation and endothelial dysfunction. TNF-α serves as one of the most important pro-inflammatory cytokines. The main objectives of the present study were to explore the effect of PKC-ζ on TNF-α-impaired endothelial function as well as the underlying mechanisms. Acetylcho-line-induced endothelium-dependent vasodilation of mouse thoracic aorta stimulated by TNF-α was initially determined. PKC-ζ deficient mice and the specific inhibitor of NADPH oxidase were respectively applied to elucidate their roles in TNF-α-induced endothelial dysfunction. In vitro superoxide generation in HAECs was detected by DHE staining after administration of TNF-α. Meanwhile, the regulatory p47phox subunit of NADPH oxidase was evaluated by Western blotting and RT-PCR. The results showed that TNF-α conspicuously impaired endothelium-dependent vasodilation and the impairment was attenuated by either depleting PKC-ζ or inhibiting NADPH oxidase. In vitro TNF-α increased superoxide production and p47phox expression in HAECs, and such increases could be ameliorated by the specific PKC-ζ inhibitor. Our findings suggest that superoxide over-production triggered by PKC-ζ-dependent NADPH oxidase activation contributes to TNF-α-induced endothelial dysfunction.展开更多
AIM:To investigate the effects of a selective inhibitor of Rho-associated kinase(ROCK),Y-27632,on inbred Wuzhishan porcine corneal endothelial cells(PCECs)in vitro and in vivo studies.METHODS:Primary PCECs were trypsi...AIM:To investigate the effects of a selective inhibitor of Rho-associated kinase(ROCK),Y-27632,on inbred Wuzhishan porcine corneal endothelial cells(PCECs)in vitro and in vivo studies.METHODS:Primary PCECs were trypsinized from Wuzhishan miniature porcine corneal tissues.The optimal concentration of Y-27632 on PCECs was determined through MTT and 5-ethynyl-2'-deoxyuridine(EdU)-labeling assays.Seven New Zealand rabbits were used as a corneal endothelial dysfunction model,and a PCECs suspension supplemented with Y-27632 was injected into the anterior chamber of the rabbits.The progression of rabbit corneal opacity and edema were observed by slit lamp examination.The rabbits were sacrificed,and rabbit globes were enucleated for trypan blue-alizarin red staining,hematoxylineosin staining,and immunofluorescence analysis.RESULTS:Administration of 100μmol/L Y-27632 facilitated PCECs'proliferation obviously.The rabbit corneas injected with PCECs suspension and 100μmol/L Y-27632 were restored to transparency significantly after 14d.CONCLUSION:The 100μmol/L Y-27632 treatment improves PCECs'proliferation significantly.And our results suggest that Y-27632 and PCECs can be used to treat corneal endothelial dysfunction.展开更多
This study aimed to compare the efficacy of four formulations of plant-based functional foods on the protection against salt-induced endothelial dysfunction.A randomized crossover design was employed.Ten healthy subje...This study aimed to compare the efficacy of four formulations of plant-based functional foods on the protection against salt-induced endothelial dysfunction.A randomized crossover design was employed.Ten healthy subjects were recruited,and on five separate occasions they received,in random sequence one of the following 5 treatments:250 mL of plain water(control)alone,and with beetroot powder,celery powder,green tea extract or beetroot powder with green tea extract prior to consuming 150 mL of high-salt chicken broth.Flow-mediated dilation(FMD),blood pressure(BP),heart rate(HR)and pulse-wave velocity(PWV)were measured at fasting and at 30,60,90 and 120 min postprandial.Comparing with control,beetroot supplementation led to a significantly increased HR at 30,60 and 90 min postprandially(P=0.025,0.004,<0.001,respectively).No significant difference was observed for FMD,BP and PWV between control and any of the treatments.Salt reduction may still be the most effective strategy to improve vascular health.展开更多
Icariin, a flavonoid glycoside, is extracted from Epimedium. This study aimed to investigate the vascular protective effects of icariin in type 1 diabetic rats by inhibiting high-mobility group box 1 (HMGB1)-related i...Icariin, a flavonoid glycoside, is extracted from Epimedium. This study aimed to investigate the vascular protective effects of icariin in type 1 diabetic rats by inhibiting high-mobility group box 1 (HMGB1)-related inflammation and exploring its potential mechanisms. The impact of icariin on vascular dysfunction was assessed in streptozotocin (STZ)-induced diabetic rats through vascular reactivity studies. Western blotting and immunofluorescence assays were performed to measure the expressions of target proteins. The release of HMGB1 and pro-inflammation cytokines were measured by enzyme-linked immunosorbent assay (ELISA). The results revealed that icariin administration enhanced acetylcholine-induced vasodilation in the aortas of diabetic rats. It also notably reduced the release of pro-inflammatory cytokines, including interleukin-8 (IL-8), IL-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) in diabetic rats and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs). The results also unveiled that the pro-inflammatory cytokines in the culture medium of HUVECs could be increased by rHMGB1. The increased release of HMGB1 and upregulated expressions of HMGB1-related inflammatory factors, including advanced glycation end products (RAGE), Toll-like receptor 4 (TLR4), and phosphorylated p65 (p-p65) in diabetic rats and HG-induced HUVECs, were remarkably suppressed by icariin. Notably, HMGB1 translocation from the nucleus to the cytoplasm in HUVECs under HG was inhibited by icariin. Meanwhile, icariin could activate G protein-coupled estrogen receptor (GPER) and sirt1. To explore the role of GPER and Sirt1 in the inhibitory effect of icariin on HMGB1 release and HMGB-induced inflammation, GPER inhibitor and Sirt1 inhibitor were used in this study. These inhibitors diminished the effects of icariin on HMGB1 release and HMGB1-induced inflammation. Specifically, the GPER inhibitor also negated the activation of Sirt1 by icariin. These findings suggest that icariin activates GPER and increases the expression of Sirt1, which in turn reduces HMGB1 translocation and release, thereby improving vascular endothelial function in type 1 diabetic rats by inhibiting inflammation.展开更多
AIM:To provide the direct evidence for the crucial role of trimethylamine N-oxide(TMAO)in vascular permeability and endothelial cell dysfunction under diabetic condition.METHODS:The role of TMAO on the in vitro biolog...AIM:To provide the direct evidence for the crucial role of trimethylamine N-oxide(TMAO)in vascular permeability and endothelial cell dysfunction under diabetic condition.METHODS:The role of TMAO on the in vitro biological effect of human retinal microvascular endothelial cells(HRMEC)under high glucose conditions was tested by a cell counting kit,wound healing,a transwell and a tube formation assay.The inflammation-related gene expression affected by TMAO was tested by real-time polymerase chain reaction(RT-PCR).The expression of the cell junction was measured by Western blotting(WB)and immunofluorescence staining.In addition,two groups of rat models,diabetic and non-diabetic,were fed with normal or 0.1%TMAO for 16wk,and their plasma levels of TMAO,vascular endothelial growth factor(VEGF),interleukin(IL)-6 and tumor necrosis factor(TNF)-αwere tested.The vascular permeability of rat retinas was measured using FITC-Dextran,and the expression of zonula occludens(ZO)-1 and claudin-5 in rat retinas was detected by WB or immunofluorescence staining.RESULTS:TMAO administration significantly increased the cell proliferation,migration,and tube formation of primary HRMEC either in normal or high-glucose conditions.RT-PCR showed elevated inflammation-related gene expression of HRMEC under TMAO stimulation,while WB or immunofluorescence staining indicated decreased cell junction ZO-1 and occludin expression after high-glucose and TMAO treatment.Diabetic rats showed higher plasma levels of TMAO as well as retinal vascular leakage,which were even higher in TMAO-feeding diabetic rats.Furthermore,TMAO administration increased the rat plasma levels of VEGF,IL-6 and TNF-αwhile decreasing the retinal expression levels of ZO-1 and claudin-5.CONCLUSION:TMAO enhances the proliferation,migration,and tube formation of HRMEC,as well as destroys their vascular integrity and tight connection.It also regulates the expression of VEGF,IL-6,and TNF-α.展开更多
Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis,while the underlying mechanism remains elusive.Here,we report that the non-canonical stimulator of interferon genes(STING)-...Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis,while the underlying mechanism remains elusive.Here,we report that the non-canonical stimulator of interferon genes(STING)-PKR-like ER kinase(PERK)pathway was significantly activated in both human and mice atherosclerotic arteries.Typically,STING activation leads to the activation of interferon regulatory factor 3(IRF3)and nuclear factor-kappa B(NF-κB)/p65,thereby facilitating IFN signals and infammation.In contrast,our study reveals the activated non-canonical STING-PERK pathway increases scaffold protein bromodomain protein 4(BRD4)expression,which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines,thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation process.Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation.Mechanistically,this pathway is triggered by leaked mitochondrial DNA(mtDNA)via mitochondrial permeability transition pore(mPTP),formed by voltage-dependent anion channel 1(VDAC1)oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation.Especially,compared to macrophages,endothelial STING activation plays a more pronounced role in atherosclerosis.We propose a non-canonical STING-PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3,NF-κB and BRD4 in inflammatory responses,which provides emerging therapeutic modalities for vascular endothelial dysfunction.展开更多
Background:Pulmonary hypertension(PH)represents a threatening pathophysiologic state that can be induced by chronic hypoxia and is characterized by extensive vascular remodeling.However,the mechanism underlying hypoxi...Background:Pulmonary hypertension(PH)represents a threatening pathophysiologic state that can be induced by chronic hypoxia and is characterized by extensive vascular remodeling.However,the mechanism underlying hypoxia-induced vascular remodeling is not fully elucidated.Methods and Results:By using quantitative polymerase chain reactions,western blotting,and immunohistochemistry,we demon-strate that the expression of N-myc downstream regulated gene-1(NDRG1)is markedly increased in hypoxia-stimulated endothelial cells in a time-dependent manner as well as in human and rat endothelium lesions.To determine the role of NDRG1 in endothelial dysfunction,we performed loss-of-function studies using NDRG1 short hairpin RNAs and NDRG1 over-expression plasmids.In vitro,silencing NDRG1 attenuated proliferation,migration,and tube formation of human pulmonary artery endothelial cells(HPAECs)un-der hypoxia,while NDRG1 over-expression promoted these behaviors of HPAECs.Mechanistically,NDRG1 can directly interact with TATA-box binding protein associated factor 15(TAF15)and promote its nuclear localization.Knockdown of TAF15 abrogated the effect of NDRG1 on the proliferation,migration and tube formation capacity of HPAECs.Bioinformatics studies found that TAF15 was involved in regulating PI3K-Akt,p53,and hypoxia-inducible factor 1(HIF-1)signaling pathways,which have been proved to be PH-related pathways.In addition,vascular remodeling and right ventricular hypertrophy induced by hypoxia were markedly alleviated in NDRG1 knock-down rats compared with their wild-type littermates.Conclusions:Taken together,our results indicate that hypoxia-induced upregulation of NDRG1 contributes to endothelial dysfunction through targeting TAF15,which ultimately contributes to the development of hypoxia-induced PH.展开更多
The prevalence of both type 2 diabetes and metabolic syndrome is increasing exponentially all over the world because of global changes in obesity, sedentary lifestyle, and the aging of the population.1 The metabolic s...The prevalence of both type 2 diabetes and metabolic syndrome is increasing exponentially all over the world because of global changes in obesity, sedentary lifestyle, and the aging of the population.1 The metabolic syndrome consists of a constellation of risk factors including obesity, glucose intolerance, hypertension, and dyslipidemia. Both metabolic syndrome and type 2 diabetes occur in the setting of insulin resistance and confer an increased risk of atherosclerosis and cardiovascular disease （CVD）. The possible role of inflanunatory cytokines and atherogenic markers in this process is still being elucidated.展开更多
Non-alcoholic fatty liver disease(NAFLD)is closely related to insulin resistance,type 2 diabetes mellitus,and obesity.It is nowadays considered a multisystem disease with a strong association with cardiovascular disea...Non-alcoholic fatty liver disease(NAFLD)is closely related to insulin resistance,type 2 diabetes mellitus,and obesity.It is nowadays considered a multisystem disease with a strong association with cardiovascular disease and arterial hypertension,which interfere with changes in the coagulation system.Coagulation disorders are common in patients with hepatic impairment and are dependent on the degree of liver damage.Patients with NAFLD may have preserved overall hemostatic profile,but many studies suggest a trend toward a procoagulant state.Hypercoagulable state in NAFLD patients may even induce progression of hepatic injury.Endothelial dysfunction is present in the systemic and portal vein circulation in NAFLD patients,and platelets are being recognized as modulators of liver diseases through various mechanisms.Through a literature review,we discuss possible disorders in the coagulation cascade and fibrinolysis,endothelial dysfunction,and platelet abnormalities in patients with NAFLD.Considering the processes and mechanisms involved in the hemostatic abnormalities associated with NAFLD,directly related to liver disease or indirectly related through inflam-matory processes and metabolic disorders,several potential therapeutic targets have been identified and reviewed here.展开更多
基金funded by the National Natural Science Foundation of China(No.81770413)Hubei Provincial Natural Science Foundation of China(No.2017CFB669).
文摘Objective Endothelial dysfunction is one candidate for triggering neointima formation after arteriovenous grafts(AVGs),but the factors mediating this process are unclear.The purpose of this study was to investigate the role of endoplasmic reticulum stress(ERS)-induced endothelial dysfunction in neointima formation following AVGs in high-fat diet(HFD)mice.Methods CCAAT-enhancer-binding protein-homologous protein(CHOP)knockout(KO)mice were created.Mice were fed with HFD to produce HFD model.AVGs model were applied in the groups of WT ND,WT HFD,and CHOP KO HFD.Human umbilical vein endothelial cells(HUVECs)were cultured with oxidized low density lipoprotein(ox-LDL)(40 mg/L)for the indicated time lengths(0,6,12,24 h).ERS inhibitor tauroursodeoxycholic acid(TUDCA)was used to block ERS.Immunohistochemical staining was used to observe the changes of ICAM1.Changes of ERS were detected by real-time RT-PCR.Protein expression levels and ERS activation were detected by Western blotting.Endothellial cell function was determined by endothelial permeability assay and transendothelial migration assay.Results HFD increased neointima formation in AVGs associated with endothelial dysfunction.At the same time,ERS was increased in endothelial cells(ECs)after AVGs in mice consuming the HFD.In vitro,ox-LDL was found to stimulate ERS,increase the permeability of the EC monolayer,and cause endothelial dysfunction.Blocking ERS with TUDCA or CHOP siRNA reversed the EC dysfunction caused by ox-LDL.In vivo,knockout of CHOP(CHOP KO)protected the function of ECs and decreased neointima formation after AVGs in HFD mice.Conclusion Inhibiting ERS in ECs could improve the function of AVGs.
文摘Ischemic stroke occurs under a variety of clinical conditions and has different pathogeneses,resulting in necrosis of brain parenchyma.Stroke pathogenesis is characterized by neuroinflammation and endothelial dysfunction.Some of the main processes triggered in the early stages of ischemic damage are the rapid activation of resident inflammatory cells(microglia,astrocytes and endothelial cells),inflammatory cytokines,and translocation of intercellular nuclear factors.Inflammation in stroke includes all the processes mentioned above,and it consists of either protective or detrimental effects concerning the“polarization”of these processes.This polarization comes out from the interaction of all the molecular pathways that regulate genome expression:the epigenetic factors.In recent years,new regulation mechanisms have been cleared,and these include non-coding RNAs,adenosine receptors,and the activity of mesenchymal stem/stromal cells and microglia.We reviewed how long non-coding RNA and microRNA have emerged as an essential mediator of some neurological diseases.We also clarified that their roles in cerebral ischemic injury may provide novel targets for the treatment of ischemic stroke.To date,we do not have adequate tools to control pathophysiological processes associated with stroke.Our goal is to review the role of non-coding RNAs and innate immune cells(such as microglia and mesenchymal stem/stromal cells)and the possible therapeutic effects of their modulation in patients with acute ischemic stroke.A better understanding of the mechanisms that influence the“polarization”of the inflammatory response after the acute event seems to be the way to change the natural history of the disease.
基金supported by the National Natural Science Foundation of China (Grant Nos.30471484 and 30972531)Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘Objective To explore the relationship of inflammation and endothelial dysfunction with risks to cardiovascular disease （CVD）. Methods Blood pressure, body weight, body height, waist circumference and lifestyle risk factors were measured and studied among 2589 participants in Inner Mongolia of China, and biomarkers of inflammation and endothelial dysfunction including high-sensitivity C-reactive protein （hsCRP）, soluble inter-cellular adhesion molecule-1 （slCAM-1）, soluble E-selectin （sE-selectin）, and angiotensin II were investigated. Results Subjects with metabolic risk factors for CVD had higher levels of hsCRP, sE-selectin and slCAM-1 than those without such risk factors （all P〈O.05）. Levels of all biomarkers positively and significantly increased with aggregation of the metabolic risk factors among the subjects （all P for trend 〈0.001）. Data from the multivariate analysis showed that participants with high levels of hsCRP [odds ratio （OR}： 1.96, 95% confidence interval （CI）： 1.52-2.53], sE-selectin （OR： 1.35, 95% Cl： 1.05-1.72）, and angiotensin II （OR： 1.81, 95% CI＂ 1.40-2.33） were more likely to develop hypertension; participants with high levels of hsCRP （OR： 2.33, 95% CI： 1.85-2.94）, sE-selectin （OR： 1.24, 95% CI： 1.00-1.54）, and slCAM-1 （OR： 1.70, 95% CI： 1.30-2.22） were more likely to develop dyslipidemia, and those with high levels of hsCRP （OR： 2.95, 95% CI： 2.27-3.83） and slCAM-I（OR： 2.80, 95% CI： 2.06-3.80） were more likely to develop hyperglycemia. Conclusion Biomarkers of inflammation and endothelial dysfunction were separately associated with relevant metabolic risk factors for CVD. And appropriate measures should be taken to control inflammation and improve endothelial function among individuals with different metabolic risk factors for CVD.
基金National Natural Science Foundation of China,No.81800244 and No.81670237.
文摘BACKGROUND Endothelial dysfunction,a hallmark of diabetes,is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications.However,the underlying mechanisms are still not fully understood.Ferroptosis is a newly defined regulated cell death driven by cellular metabolism and irondependent lipid peroxidation.Although the involvement of ferroptosis in disease pathogenesis has been shown in cancers and degenerative diseases,the participation of ferroptosis in the pathogenesis of diabetic endothelial dysfunction remains unclear.AIM To examine the role of ferroptosis in diabetes-induced endothelial dysfunction and the underlying mechanisms.METHODS Human umbilical vein endothelial cells(HUVECs)were treated with high glucose(HG),interleukin-1β(IL-1β),and ferroptosis inhibitor,and then the cell viability,reactive oxygen species(ROS),and ferroptosis-related marker protein were tested.To further determine whether the p53-xCT(the substrate-specific subunit of system Xc-)-glutathione(GSH)axis is involved in HG and IL-1βinduced ferroptosis,HUVECs were transiently transfected with p53 small interfering ribonucleic acid or NC small interfering ribonucleic acid and then treated with HG and IL-1β.Cell viability,ROS,and ferroptosis-related marker protein were then assessed.In addition,we detected the xCT and p53 expression in the aorta of db/db mice.RESULTS It was found that HG and IL-1βinduced ferroptosis in HUVECs,as evidenced by the protective effect of the ferroptosis inhibitors,Deferoxamine and ferrostatin-1,resulting in increased lipid ROS and decreased cell viability.Mechanistically,activation of the p53-xCT-GSH axis induced by HG and IL-1βenhanced ferroptosis in HUVECs.In addition,a decrease in xCT and the presence of deendothelialized areas were observed in the aortic endothelium of db/db mice.CONCLUSION Ferroptosis is involved in endothelial dysfunction and p53-xCT-GSH axis activation plays a crucial role in endothelial cell ferroptosis and endothelial dysfunction.
文摘Microparticles are small cell vesicles that can be released by almost all eukaryotic cells during cellular stress and cell activation. Within the last 1-2 decades it has been shown that microparticles are useful blood surrogate markers for different pathological conditions, such as vascular inflammation, coagulation and tumour diseases. Several studies have investigated the abundance of microparticles of different cellular origins in multiple cardiovascular diseases. It thereby has been shown that microparticles released by platelets, leukocytes and endothelial cells can be found in conditions of endothelial dysfunction, acute and chronic vascular inflammation and hypercoagulation. In addition to their function as surrogate markers, several studies indicate that circulating microparticles can fuse with distinct target cells, such as endothelial cells or leukocyte, and thereby deliver cellular components of their parental cells to the target cells. Hence, microparticles are a novel entity of circulating, paracrine, biological vectors which can influence the phenotype, the function and presumably even the transcriptome of their target cells.This review article aims to give a brief overview about the microparticle biology with a focus on endothelial activation and arterial hypertension. More detailed information about the role of microparticles in pathophysiology and disease can be found in already published work.
文摘Metabolic syndrome is a cluster of several clinical conditions characterized by insulin-resistance and high cardiovascular risk. Non-alcoholic fatty liver disease is the liver expression of the metabolic syndrome, and insulin resistance can be a frequent comorbidity in several chronic liver diseases, in particular hepatitis C virus infection and/or cirrhosis. Several studies have demonstrated that insulin action is not only relevant for glucose control, but also for vascular homeostasis. Insulin regulates nitric oxide production, which mediates to a large degree the vasodilating, antiinflammatory and antithrombotic properties of a healthy endothelium, guaranteeing organ perfusion. The effects of insulin on the liver microvasculature and the effects of IR on sinusoidal endothelial cells have been studied in animal models of non-alcoholic fatty liver disease. The hypotheses derived from these studies and the potential translation of these results into humans are critically discussed in this review.
文摘Postprandial hyperglycemia has been reported to elicit endothelial dysfunction and provoke future cardiovascular complications. A reduction of postprandial blood glucose levels by the glucosidase inhibitor Fuscoporia obliqua was associated with a risk reduction of cardiovascular complications, but the effects of Fuscoporia obliqua on endothelial function have never been elucidated. This study is aimed to assess the efficacy of Fuscoporia obliqua on postprandial metabolic parameters and endothelial function in type 2 diabetic patients. Postprandial peak glucose (14.47±1.27 vs. 8.50±0.53 mmol/liter), plasma glucose excursion (PPGE), and change in the area under the curve (AUC) glucose after a single loading of test meal (total 450 kcal; protein 15.3%; fat 32.3%; carbohydrate 51.4%) were significantly higher in the diet-treated type 2 diabetic patients (n=14) than the age-and sex-matched controls (n=12). The peak forearm blood flow response and total reactive hyperemic flow (flow debt repayment) during reactive hyperemia, indices of resistance artery endothelial function on strain-gauge plethysmography, were unchanged before and after meal loading in the controls. But those of the diabetics were significantly decreased 120 and 240 min after the test meal. A prior administration of Fuscoporia obliqua decreased postprandial peak glucose, PPGE, and AUC glucose. The peak forearm blood flow and flow debt repayment were inversely well correlated with peak glucose, PPGE, and AUC glucose, but not with AUC insulin or the other lipid parameters. Even a single loading of the test meal was shown to impair the endothelial function in type 2 diabetic patients, and the postprandial endothelial dysfunction was improved by a prior use of Fuscoporia obliqua. Fuscoporia obliqua might reduce macrovascular complication by avoiding endothelial injury in postprandial hyperglycemic status.
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(81230082,81302771,81525025,81573422,81500226)Natural Science Foundation of Guangdong Province(2014A030313087)by Science and Technology program of Guangzhou City(201607010255)
文摘OBJECTIVE The Ca2+-activated Cl-channel(Ca CC)plays a crucial role in various physiological functions.Recent evidences suggest TMEM16A encodes CaC C in various cells,including endothelial cells.However,the role of TMEM16A in the vascular endothelial dysfunction in hypertension is unclear.METHODS In the study,RT-PCR,Western blotting,co-immunopricipitation,confocal imaging,patch-clamp,and endothelial-specific TMEM16A transgenic and knockout mice were employed.RESULTS We found that TMEM16A was expressed abundantly and functioned as Ca CC in endothelial cells.AngiotensinⅡ(AngⅡ)induced endothelial dysfunction with an increase in TMEM16A expression,which was alleviated by TMEM16A inhibitor.Further studies revealed that TMEM16A endothelial-specific knockout significantly lowered the blood pressure and ameliorated endothelial dysfunction in AngⅡ-induced hypertension,whereas,TMEM16A endothelial-specific overexpression showed the opposite effects.These results were related to the increased reactive oxygen species(ROS)generation,NADPH oxidase activation,and Nox2,p22phox expression facilitated by TMEM16A upon AngⅡ-induced hypertensive challenges.Moreover,TMEM16A directly interacted with Nox2 monomer and reduced the degradation of Nox2 through the proteasome-dependent endoplasmic recticulum-associated degradation pathway.TMEM16A also potentiated the translocation of p47phox and p67phox from cytosol to cell membrane and the subsequent interaction with Nox2.CONCLUSION Our results demonstrated that TMEM16A,as Ca CC,is a positive regulator of ROS generation via upregulating the activation of Nox2 NADPH oxidase in the vascular endothelium,and therefore facilitates endothelial dysfunction and hypertension.Modification of TMEM16A may be a novel therapeutic strategy for endothelial dysfunction-associated cardiovascular diseases.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81100814,No.91539202,No.81230071 and No.81571630)the Shanghai Municipal Commission of Health and Farmily Planning(No.201540222 and No.2017YQ076).
文摘Vascular remodeling is an adaptive response to various stimuli,including mechanical forces,inflammatory cy tokines and hormones.In the present study,we investigated the role of angiotensinII type 1 receptor(ATIR)and calcium channel in carotid artery remodeling in response to increased biomechanical forces by using the transverse aortic constriction(TAC)rat model.TAC was induced on ten week-old male Sprague Dawley rats and these models were treated with ATIR blocker olmesartan(1 mg/kg/day)or/and calcium channel blocker(CCB)amlodipine(0.5 mgkgday)for 14 days.After the treatment,the right common carotid artery proximal to the band(RCCA-B)was collected for further assay.Results showed that olmesartan,but not amlodipine,significantly prevented TAC-induced adventitial hyperplasia.Similarly,olmesartan,but not amlodipine,significantly prevented vascular inflammation,as indicated by increased tumor necrosis factor a(TNF-a)and increased p65 phosphorylation,an indicator of nuclear factor K-light-chain-enhancer of activated B cells(NFkB)activation in RCCA-B.In contrast,both olmesartan and amlodipine reversed the decreased expression of endothelial nitric oxidase synthase(eNOS)and improved endothelium-dependent vasodilation,whereas combination of olmesartan and amlodipine showed no further synergistic protective effects.These results suggest that AT1R was involved in vascular remodeling and inflammation in response to pressure overload,whereas ATIR and subsequent calcium channel were involved in endothelial dysfunction.
文摘Background Endothelial dysfunction is the initial stage in atherosclerotic formation and progression and is associated with high serum uric acid(SUA)level.We hypothesized that reactive hyperemia index(RHI),which reflects endothelial function,is associated with SUA levels in elderly individuals with untreated mild hypertension.Methods We recruited 123 patients≥60 years with untreated mild hypertension.The association between SUA level and RHI was analyzed using univariate correlation analysis and multiple regression analysis.The receiver operating characteristic(ROC)curve was performed to validate the cutoff value of SUA that can be used to predict endothelial dysfunction.Results The serum uric acid level significantly increased in the RHI<1.67 group,and this result was still observed in the subgroup of men.RHI was inversely associated with SUA level(P=0.006)and the association was still observed after adjusting for factors,such as age,sex,smoking status,and creatinine level(P=0.014).In the subgroup analysis,a positive association was observed only in men.In the ROC curve analysis,the optimal cutoff values of SUA for predicting endothelial dysfunction was 293.5μmol/L in elderly mild hypertension patients and 287.0μmol/L in men.Conclusion A high SUA level was considered an independent predictor of endothelial dysfunction among elderly individuals,particularly men with untreated mild hypertension.
文摘Endothelial dysfunction is implicated in a variety of cardiovascular diseases although the detailed mechanisms are not yet completely understood. A relationship has been suggested to exist between inflammation and endothelial dysfunction. TNF-α serves as one of the most important pro-inflammatory cytokines. The main objectives of the present study were to explore the effect of PKC-ζ on TNF-α-impaired endothelial function as well as the underlying mechanisms. Acetylcho-line-induced endothelium-dependent vasodilation of mouse thoracic aorta stimulated by TNF-α was initially determined. PKC-ζ deficient mice and the specific inhibitor of NADPH oxidase were respectively applied to elucidate their roles in TNF-α-induced endothelial dysfunction. In vitro superoxide generation in HAECs was detected by DHE staining after administration of TNF-α. Meanwhile, the regulatory p47phox subunit of NADPH oxidase was evaluated by Western blotting and RT-PCR. The results showed that TNF-α conspicuously impaired endothelium-dependent vasodilation and the impairment was attenuated by either depleting PKC-ζ or inhibiting NADPH oxidase. In vitro TNF-α increased superoxide production and p47phox expression in HAECs, and such increases could be ameliorated by the specific PKC-ζ inhibitor. Our findings suggest that superoxide over-production triggered by PKC-ζ-dependent NADPH oxidase activation contributes to TNF-α-induced endothelial dysfunction.
基金Supported by National Natural Science Foundation of China(No.81470608)。
文摘AIM:To investigate the effects of a selective inhibitor of Rho-associated kinase(ROCK),Y-27632,on inbred Wuzhishan porcine corneal endothelial cells(PCECs)in vitro and in vivo studies.METHODS:Primary PCECs were trypsinized from Wuzhishan miniature porcine corneal tissues.The optimal concentration of Y-27632 on PCECs was determined through MTT and 5-ethynyl-2'-deoxyuridine(EdU)-labeling assays.Seven New Zealand rabbits were used as a corneal endothelial dysfunction model,and a PCECs suspension supplemented with Y-27632 was injected into the anterior chamber of the rabbits.The progression of rabbit corneal opacity and edema were observed by slit lamp examination.The rabbits were sacrificed,and rabbit globes were enucleated for trypan blue-alizarin red staining,hematoxylineosin staining,and immunofluorescence analysis.RESULTS:Administration of 100μmol/L Y-27632 facilitated PCECs'proliferation obviously.The rabbit corneas injected with PCECs suspension and 100μmol/L Y-27632 were restored to transparency significantly after 14d.CONCLUSION:The 100μmol/L Y-27632 treatment improves PCECs'proliferation significantly.And our results suggest that Y-27632 and PCECs can be used to treat corneal endothelial dysfunction.
基金funded by the Seed Funding for Translational and Applied Research,University Grants Council,The University of Hong Kong(Ref:201611160038)。
文摘This study aimed to compare the efficacy of four formulations of plant-based functional foods on the protection against salt-induced endothelial dysfunction.A randomized crossover design was employed.Ten healthy subjects were recruited,and on five separate occasions they received,in random sequence one of the following 5 treatments:250 mL of plain water(control)alone,and with beetroot powder,celery powder,green tea extract or beetroot powder with green tea extract prior to consuming 150 mL of high-salt chicken broth.Flow-mediated dilation(FMD),blood pressure(BP),heart rate(HR)and pulse-wave velocity(PWV)were measured at fasting and at 30,60,90 and 120 min postprandial.Comparing with control,beetroot supplementation led to a significantly increased HR at 30,60 and 90 min postprandially(P=0.025,0.004,<0.001,respectively).No significant difference was observed for FMD,BP and PWV between control and any of the treatments.Salt reduction may still be the most effective strategy to improve vascular health.
基金supported by the National New Drug Innovation Program of China(No.2017ZX09301004)the National Natural Science Foundation of China(No.81873131)。
文摘Icariin, a flavonoid glycoside, is extracted from Epimedium. This study aimed to investigate the vascular protective effects of icariin in type 1 diabetic rats by inhibiting high-mobility group box 1 (HMGB1)-related inflammation and exploring its potential mechanisms. The impact of icariin on vascular dysfunction was assessed in streptozotocin (STZ)-induced diabetic rats through vascular reactivity studies. Western blotting and immunofluorescence assays were performed to measure the expressions of target proteins. The release of HMGB1 and pro-inflammation cytokines were measured by enzyme-linked immunosorbent assay (ELISA). The results revealed that icariin administration enhanced acetylcholine-induced vasodilation in the aortas of diabetic rats. It also notably reduced the release of pro-inflammatory cytokines, including interleukin-8 (IL-8), IL-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) in diabetic rats and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs). The results also unveiled that the pro-inflammatory cytokines in the culture medium of HUVECs could be increased by rHMGB1. The increased release of HMGB1 and upregulated expressions of HMGB1-related inflammatory factors, including advanced glycation end products (RAGE), Toll-like receptor 4 (TLR4), and phosphorylated p65 (p-p65) in diabetic rats and HG-induced HUVECs, were remarkably suppressed by icariin. Notably, HMGB1 translocation from the nucleus to the cytoplasm in HUVECs under HG was inhibited by icariin. Meanwhile, icariin could activate G protein-coupled estrogen receptor (GPER) and sirt1. To explore the role of GPER and Sirt1 in the inhibitory effect of icariin on HMGB1 release and HMGB-induced inflammation, GPER inhibitor and Sirt1 inhibitor were used in this study. These inhibitors diminished the effects of icariin on HMGB1 release and HMGB1-induced inflammation. Specifically, the GPER inhibitor also negated the activation of Sirt1 by icariin. These findings suggest that icariin activates GPER and increases the expression of Sirt1, which in turn reduces HMGB1 translocation and release, thereby improving vascular endothelial function in type 1 diabetic rats by inhibiting inflammation.
基金Supported by the National Natural Science Foundation in China(No.81671641)Jiangsu Provincial Medical Innovation Team(No.CXTDA2017039)Gusu Health Talents Program(No.GSWS 2022018).
文摘AIM:To provide the direct evidence for the crucial role of trimethylamine N-oxide(TMAO)in vascular permeability and endothelial cell dysfunction under diabetic condition.METHODS:The role of TMAO on the in vitro biological effect of human retinal microvascular endothelial cells(HRMEC)under high glucose conditions was tested by a cell counting kit,wound healing,a transwell and a tube formation assay.The inflammation-related gene expression affected by TMAO was tested by real-time polymerase chain reaction(RT-PCR).The expression of the cell junction was measured by Western blotting(WB)and immunofluorescence staining.In addition,two groups of rat models,diabetic and non-diabetic,were fed with normal or 0.1%TMAO for 16wk,and their plasma levels of TMAO,vascular endothelial growth factor(VEGF),interleukin(IL)-6 and tumor necrosis factor(TNF)-αwere tested.The vascular permeability of rat retinas was measured using FITC-Dextran,and the expression of zonula occludens(ZO)-1 and claudin-5 in rat retinas was detected by WB or immunofluorescence staining.RESULTS:TMAO administration significantly increased the cell proliferation,migration,and tube formation of primary HRMEC either in normal or high-glucose conditions.RT-PCR showed elevated inflammation-related gene expression of HRMEC under TMAO stimulation,while WB or immunofluorescence staining indicated decreased cell junction ZO-1 and occludin expression after high-glucose and TMAO treatment.Diabetic rats showed higher plasma levels of TMAO as well as retinal vascular leakage,which were even higher in TMAO-feeding diabetic rats.Furthermore,TMAO administration increased the rat plasma levels of VEGF,IL-6 and TNF-αwhile decreasing the retinal expression levels of ZO-1 and claudin-5.CONCLUSION:TMAO enhances the proliferation,migration,and tube formation of HRMEC,as well as destroys their vascular integrity and tight connection.It also regulates the expression of VEGF,IL-6,and TNF-α.
基金supported by the National Nature Science Foundation of China(82270421,81970428,31771334,81800385,82270484,81873654,31800971,and 82170503)the Major Research Plan of the National Natural Science Foundation of China(91649125)+5 种基金University Natural Science Research of Jiangsu Province(18KJB310008,China)Natural Science Foundation of Jiangsu Province(BK20180684,China)supported by the program of special professor of Jiangsu Provincethe program of the special medical experts of Jiangsu Provincethe program of innovation and entrepreneurship team plan of Jiangsu ProvinceMajor project supported by the Basic Science(Natural Science)Foundation of the Jiangsu Higher Education Institutions,Jiangsu Provincial Social Development Project(BE2021749,China).
文摘Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis,while the underlying mechanism remains elusive.Here,we report that the non-canonical stimulator of interferon genes(STING)-PKR-like ER kinase(PERK)pathway was significantly activated in both human and mice atherosclerotic arteries.Typically,STING activation leads to the activation of interferon regulatory factor 3(IRF3)and nuclear factor-kappa B(NF-κB)/p65,thereby facilitating IFN signals and infammation.In contrast,our study reveals the activated non-canonical STING-PERK pathway increases scaffold protein bromodomain protein 4(BRD4)expression,which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines,thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation process.Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation.Mechanistically,this pathway is triggered by leaked mitochondrial DNA(mtDNA)via mitochondrial permeability transition pore(mPTP),formed by voltage-dependent anion channel 1(VDAC1)oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation.Especially,compared to macrophages,endothelial STING activation plays a more pronounced role in atherosclerosis.We propose a non-canonical STING-PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3,NF-κB and BRD4 in inflammatory responses,which provides emerging therapeutic modalities for vascular endothelial dysfunction.
基金supported by the National Natural Science Foundation of China(Grants No.81970048,82270058)starting fund for scientific research of Huashan Hospital Fudan University(Grant No.2017QD078).
文摘Background:Pulmonary hypertension(PH)represents a threatening pathophysiologic state that can be induced by chronic hypoxia and is characterized by extensive vascular remodeling.However,the mechanism underlying hypoxia-induced vascular remodeling is not fully elucidated.Methods and Results:By using quantitative polymerase chain reactions,western blotting,and immunohistochemistry,we demon-strate that the expression of N-myc downstream regulated gene-1(NDRG1)is markedly increased in hypoxia-stimulated endothelial cells in a time-dependent manner as well as in human and rat endothelium lesions.To determine the role of NDRG1 in endothelial dysfunction,we performed loss-of-function studies using NDRG1 short hairpin RNAs and NDRG1 over-expression plasmids.In vitro,silencing NDRG1 attenuated proliferation,migration,and tube formation of human pulmonary artery endothelial cells(HPAECs)un-der hypoxia,while NDRG1 over-expression promoted these behaviors of HPAECs.Mechanistically,NDRG1 can directly interact with TATA-box binding protein associated factor 15(TAF15)and promote its nuclear localization.Knockdown of TAF15 abrogated the effect of NDRG1 on the proliferation,migration and tube formation capacity of HPAECs.Bioinformatics studies found that TAF15 was involved in regulating PI3K-Akt,p53,and hypoxia-inducible factor 1(HIF-1)signaling pathways,which have been proved to be PH-related pathways.In addition,vascular remodeling and right ventricular hypertrophy induced by hypoxia were markedly alleviated in NDRG1 knock-down rats compared with their wild-type littermates.Conclusions:Taken together,our results indicate that hypoxia-induced upregulation of NDRG1 contributes to endothelial dysfunction through targeting TAF15,which ultimately contributes to the development of hypoxia-induced PH.
文摘The prevalence of both type 2 diabetes and metabolic syndrome is increasing exponentially all over the world because of global changes in obesity, sedentary lifestyle, and the aging of the population.1 The metabolic syndrome consists of a constellation of risk factors including obesity, glucose intolerance, hypertension, and dyslipidemia. Both metabolic syndrome and type 2 diabetes occur in the setting of insulin resistance and confer an increased risk of atherosclerosis and cardiovascular disease （CVD）. The possible role of inflanunatory cytokines and atherogenic markers in this process is still being elucidated.
文摘Non-alcoholic fatty liver disease(NAFLD)is closely related to insulin resistance,type 2 diabetes mellitus,and obesity.It is nowadays considered a multisystem disease with a strong association with cardiovascular disease and arterial hypertension,which interfere with changes in the coagulation system.Coagulation disorders are common in patients with hepatic impairment and are dependent on the degree of liver damage.Patients with NAFLD may have preserved overall hemostatic profile,but many studies suggest a trend toward a procoagulant state.Hypercoagulable state in NAFLD patients may even induce progression of hepatic injury.Endothelial dysfunction is present in the systemic and portal vein circulation in NAFLD patients,and platelets are being recognized as modulators of liver diseases through various mechanisms.Through a literature review,we discuss possible disorders in the coagulation cascade and fibrinolysis,endothelial dysfunction,and platelet abnormalities in patients with NAFLD.Considering the processes and mechanisms involved in the hemostatic abnormalities associated with NAFLD,directly related to liver disease or indirectly related through inflam-matory processes and metabolic disorders,several potential therapeutic targets have been identified and reviewed here.
