Pericytes are the main cellular components of tiny arteries and capillaries.Studies have found that pericytes can undergo morphological contraction or relaxation under stimulation by cytokines,thus affecting the contr...Pericytes are the main cellular components of tiny arteries and capillaries.Studies have found that pericytes can undergo morphological contraction or relaxation under stimulation by cytokines,thus affecting the contraction and relaxation of microvessels and playing an essential role in regulating vascular microcirculation.Moreover,due to the characteristics of stem cells,pericytes can differentiate into a variety of inflammatory cell phenotypes,which then affect the immune function.Additionally,pericytes can also participate in angiogenesis and wound healing by interacting with endothelial cells in vascular microcirculation disorders.Here we review the origin,biological phenotype and function of pericytes,and discuss the potential mechanisms of pericytes in vascular microcirculation disorders,especially in pulmonary hypertension,so as to provide a sound basis and direction for the prevention and treatment of vascular microcirculation diseases.展开更多
Background:Circular RNAs(circRNAs)have been recognized as significant regulators of pulmonary hypertension(PH);however,the differential expression and function of circRNAs in different vascular cells under hypoxia rem...Background:Circular RNAs(circRNAs)have been recognized as significant regulators of pulmonary hypertension(PH);however,the differential expression and function of circRNAs in different vascular cells under hypoxia remain unknown.Here,we identified co-differentially expressed circRNAs and determined their putative roles in the proliferation of pulmonary artery smooth muscle cells(PASMCs),pulmonary microvascular endothelial cells(PMECs),and pericytes(PCs)under hypoxia.Methods:Whole transcriptome sequencing was performed to analyze the differential expression of circRNAs in three different vascular cell types.Bioinformatic analysis was used to predict their putative biological function.Quantitative real-time polymerase chain reaction,Cell Counting Kit-8,and EdU Cell Proliferation assays were carried out to determine the role of circular postmeiotic segregation 1(circPMS1)as well as its potential sponge mechanism in PASMCs,PMECs,and PCs.Results:PASMCs,PMECs,and PCs exhibited 16,99,and 31 differentially expressed circRNAs under hypoxia,respectively.CircPMS1 was upregulated in PASMCs,PMECs,and PCs under hypoxia and enhanced the proliferation of vascular cells.CircPMS1may upregulate DEP domain containing 1(DEPDC1)and RNA polymerase II subunit D expression by targeting microRNA-432-5p(miR-432-5p)in PASMCs,upregulate MAX interactor 1(MXI1)expression by targeting miR-433-3p in PMECs,and upregulate zinc finger AN1-type containing 5(ZFAND5)expression by targeting miR-3613-5p in PCs.Conclusions:Our results suggest that circPMS1 promotes cell proliferation through the miR-432-5p/DEPDC1 or miR-432-5p/POL2D axis in PASMCs,through the miR-433-3p/MXI1 axis in PMECs,and through the miR-3613-5p/ZFAND5 axis in PCs,which provides putative targets for the early diagnosis and treatment of PH.展开更多
Background:Our previous study found that mouse embryonic neural stem cell(NSC)-derived exosomes(EXOs)regulated NSC differentiation via the miR-9/Hes1 axis.However,the effects of EXOs on brain microvascular endothelial...Background:Our previous study found that mouse embryonic neural stem cell(NSC)-derived exosomes(EXOs)regulated NSC differentiation via the miR-9/Hes1 axis.However,the effects of EXOs on brain microvascular endothelial cell(BMEC)dysfunction via the miR-9/Hes1 axis remain unknown.Therefore,the current study aimed to determine the effects of EXOs on BMEC proliferation,migration,and death via the miR-9/Hes1 axis.Methods:Immunofluorescence,quantitative real-time polymerase chain reaction,cell counting kit-8 assay,wound healing assay,calcein-acetoxymethyl/propidium iodide staining,and hematoxylin and eosin staining were used to determine the role and mechanism of EXOs on BMECs.Results:EXOs promoted BMEC proliferation and migration and reduced cell death under hypoxic conditions.The overexpression of miR-9 promoted BMEC prolifera-tion and migration and reduced cell death under hypoxic conditions.Moreover,miR-9 downregulation inhibited BMEC proliferation and migration and also promoted cell death.Hes1 silencing ameliorated the effect of amtagomiR-9 on BMEC proliferation and migration and cell death.Hyperemic structures were observed in the regions of the hippocampus and cortex in hypoxia-induced mice.Meanwhile,EXO treatment improved cerebrovascular alterations.Conclusion:NSC-derived EXOs can promote BMEC proliferation and migra-tion and reduce cell death via the miR-9/Hes1 axis under hypoxic conditions.Therefore,EXO therapeutic strategies could be considered for hypoxia-induced vascular injury.展开更多
Background:The maintenance dosage of selexipag is categorized as low,medium or high.In order to assess the efficacy and safety of different dosages of selexipag for the risk stratification of pulmonary arterial hypert...Background:The maintenance dosage of selexipag is categorized as low,medium or high.In order to assess the efficacy and safety of different dosages of selexipag for the risk stratification of pulmonary arterial hypertension(PAH),we performed a sys-tematic review and meta-analysis.Methods:Studies assessing PAH risk stratification indices,such as the World Health Organization functional class(WHO-FC),six-minute walk distance(6MWD),N-terminal pro-B-type natriuretic peptide(NT-proBNP)level,right atrial pressure(RAP),cardiac index(CI)and mixed venous oxygen saturation(SvO2),were included.Results:Thirteen studies were included.Selexipag led to improvements in the 6MWD(MD:24.20 m,95%CI:10.74-37.67),NT-proBNP(SMD:-0.41,95%CI:-0.79-0.04),CI(MD:0.47 L/min/m^(2),95%CI:0.17-0.77)and WHO-FC(OR:0.564,95%CI:0.457-0.697).Subgroup analysis demonstrated that all three dosages improved the 6MWD.A moderate dosage led to improvements in the CI(MD:0.30 L/min/m^(2),95%CI:0.15-0.46)and WHO-FC(OR:0.589,95%CI:0.376-0.922).Within 6 months of treatment,only the WHO-FC and CI were significantly improved(OR:0.614,95%CI:0.380-0.993;MD:0.30 L/min/m^(2),95%CI:0.16-0.45,respectively).More than 6 months of treatment significantly improved the 6MWD,WHO-FC and NT-proBNP(MD:40.87 m,95%CI:10.97-70.77;OR:0.557,95%CI:0.440-0.705;SMD:-0.61,95%CI:-1.17-0.05,respectively).Conclusions:Low,medium,and high dosages of selexipag all exhibited good effects.When treatment lasted for more than 6 months,selexipag exerted obvious effects,even in the low-dosage group.This finding is important for guiding individualized treatments.展开更多
Circular RNAs(circRNAs)are endogenous RNAs with a covalently closed single-stranded transcript.They are a novel class of genomic regulators that are linked to many important development and disease processes and are b...Circular RNAs(circRNAs)are endogenous RNAs with a covalently closed single-stranded transcript.They are a novel class of genomic regulators that are linked to many important development and disease processes and are being pursued as clinical and therapeutic targets.Using the most powerful RNA sequencing and bioinformatics techniques,a large number of circRNAs have been identified and further functional studies have been performed.It is known that circRNAs act as potential biomarkers,sponges for microRNAs(miRNAs)and RNA-binding proteins(RBPs),and regulators of mRNA transcription.They also participate in the translation of peptides or proteins.Many types of circRNAs are dysregulated in plasma or lung tissues,and they may be involved in regulating the proliferation and apoptosis of pulmonary artery endothelial cells(PAECs)and pulmonary artery smooth muscle cells(PASMCs),leading to pulmonary vascular remodeling in pulmonary hypertension(PH).One possible mechanism is that circRNAs can regulate the function of PAECs and PASMCs by acting as miRNA sponge.However,other potential mechanisms of action of circRNAs are still being actively explored in PH.This paper presents a systematic review of the biogenesis,biological characterization,relevant underlying functions,and future perspectives for studies of circRNAs in the pathogenesis of PH.展开更多
Prolactin(PRL)is a polypeptide hormone that is mainly synthesized and secreted by the lactotroph cells of the pituitary.There are two main isoforms of PRL:23-kDa PRL(named full-l ength PRL)and vasoinhibins(including ...Prolactin(PRL)is a polypeptide hormone that is mainly synthesized and secreted by the lactotroph cells of the pituitary.There are two main isoforms of PRL:23-kDa PRL(named full-l ength PRL)and vasoinhibins(including 5.6–18 kDa fragments).Both act as circulating hormones and cytokines to stimulate or inhibit vascular formation at different stages and neovascularization,including endothelial cell proliferation and migration,protease production,and apoptosis.However,their effects on vascular function and cardiovascular diseases are different or even contrary.In addition to the structure,secretion regulation,and signal transduction of PRL/vasoinhibins,this review focuses on the pathological mechanism and clinical significance of PRL/vasoinhibins in cardiovascular diseases.展开更多
Background:Aberrant expression of microRNAs(miRNAs)has been associated with the pathogenesis of pulmonary hypertension(PH).It is,however,not clear whether miRNAs are involved in estrogen rescue of PH.Methods:Fresh pla...Background:Aberrant expression of microRNAs(miRNAs)has been associated with the pathogenesis of pulmonary hypertension(PH).It is,however,not clear whether miRNAs are involved in estrogen rescue of PH.Methods:Fresh plasma samples were prepared from 12 idiopathic pulmonary arterial hypertension(IPAH)patients and 12 healthy controls undergoing right heart cath-eterization in Shanghai Pulmonary Hospital.From each sample,5μg of total RNA was tagged and hybridized on microRNA microarray chips.Monocrotaline-induced PH(MCT-PH)male rats were treated with 17β-estradiol(E_(2))or vehicle.Subgroups were cotreated with estrogen receptor(ER)antagonist or with antagonist of miRNA.Results:Many circulating miRNAs,including miR-21-5p and miR-574-5p,were mark-edly expressed in patients and of interest in predicting mean pulmonary arterial pres-sure elevation in patients.The expression of miR-21-5p in the lungs was significantly upregulated in MCT-PH rats compared with the controls.However,miR-574-5p showed no difference in the lungs of MCT-PH rats and controls.miR-21-5p was se-lected for further analysis in rats as E_(2) strongly regulated it.E_(2) decreased miR-21-5p expression in the lungs of MCT-PH rats by ERβ.E_(2) reversed miR-21-5p target gene FilGAP downregulation in the lungs of MCT-PH rats.The abnormal expression of RhoA,ROCK2,Rac1 and c-Jun in the lungs of MCT-PH rats was inhibited by E_(2) and miR-21-5p antagonist.Conclusions:miR-21-5p level was remarkably associated with PH severity in patients.Moreover,the miR-21-5p/FilGAP signaling pathway modulated the protective effect of E_(2) on MCT-PH through ERβ.展开更多
The association between blood eosinophil(EOS)counts and arterial/venous throm-bosis is unclear.We aim to explore whether EOS count is a risk factor for throm-bosis.We searched several databases and preprint platforms ...The association between blood eosinophil(EOS)counts and arterial/venous throm-bosis is unclear.We aim to explore whether EOS count is a risk factor for throm-bosis.We searched several databases and preprint platforms using core terms‘eosinophil’,‘myocardial infarction’,‘ischemic stroke’,and‘venous thromboembo-lism’(VTE),among others.Studies comparing the odds ratios(ORs)or risk ratios(RRs)of EOSs with the abovementioned diseases were eligible.Overall,22 studies were included.A high EOS count was associated with acute coronary artery throm-bosis events(OR:1.23,95%CI:1.15-1.32),short-term cerebral infarction and mor-tality(RR:2.87,95%CI:1.49-5.51).The short-term risk of VTE was more common in patients with EOS-related diseases(RR:6.52,95%CI:2.42-17.54).For coronary artery disease,a high EOS count was a protective factor against 6-month to 1-year mortality(RR:0.56,95%CI:0.45-0.69)but was associated with long-term mortal-ity(RR:1.64,95%CI:1.25-2.14).Therefore,we conclude that for coronary artery thrombosis,EOS count is not associated with AMI events in general population.It may be associated with NSTEMI and STEMI in CAD patients,but more studies are needed to confirm this.In addition,EOS count is associated with an increased risk of both short-and long-term mortality but is not predictive of the composite end-points.For cerebral artery thrombosis,EOS count may be associated with cerebral infarction and could lead to an increased risk of poor short-term prognosis.For VTEs,EOS count was a risk factor for some patients,especially those with acute-phase EOS-related diseases.展开更多
Objective/Background:Proliferation is a widely recognized trigger for pulmonary hypertension(PH),a life-threatening,progressive disorder of pulmonary blood vessels.This study was aimed to identify some proliferation a...Objective/Background:Proliferation is a widely recognized trigger for pulmonary hypertension(PH),a life-threatening,progressive disorder of pulmonary blood vessels.This study was aimed to identify some proliferation associated genes/targets for better comprehension of PH pathogenesis.Methods:Human pulmonary arterial smooth muscle cells(hPASMCs)were cultured in the presence or absence of human recombinant platelet derived growth factor(rhPDGF)-BB.Cells were collected for metabolomics or transcriptomics study.Gene profiling of lungs of PH rats after hypoxia exposure or of PH patients were retrieved from GEO database.Results:90 metabolites(VIP score>1,fold change>2 or<0.5 and p<.05)and 2701 unique metabolism associated genes(MAGs)were identified in rhPDGF-BB treated hPASMCs compared to control cells.In addition,1151 differentially expressed genes(313 upregulated and 838 downregulated)were identified in rhPDGF-BB treated hPASMCs compared to control cells(fold change>2 or<0.5 and p<.05).152 differentially expressed MAGs were then determined,out of which 9 hub genes(IL6,CXCL8,CCL2,CXCR4,CCND1,PLAUR,PLAU,HBEGF and F3)were defined as core proliferation associated hub genes in protein proten interaction analysis.In addition,the hub gene-based LASSO model can predict the occurrence of PH(AUC=0.88).The expression of CXCR4,as one of the hub genes,was positively correlated to immune cell infiltrates.Conclusion:Our findings revealed some key proliferation associated genes in PH,which provide the crucial information concerning complex metabolic reprogramming and inflammatory modulation in response to proliferation signals and might offer therapeutic gains for PH.展开更多
To the Editor:Obesity,which has currently become an important public health problem,has been considered a positive prognostic factor for patients with multiple chronic disorders,including pulmonary arterial hypertensi...To the Editor:Obesity,which has currently become an important public health problem,has been considered a positive prognostic factor for patients with multiple chronic disorders,including pulmonary arterial hypertension,a phenomenon known as the“obesity paradox”.[1]However,whether this phenomenon exists in pulmonary hypertension(PH)secondary to chronic lung disease(CLD-PH)remains unknown.This study aimed to elucidate the association between body mass index(BMI)and mortality in CLD-PH patients.展开更多
Dear Editor,Major depressive disorder(MDD)is one of the most common psychiatric illnesses that significantly increase the risk of suicide.1 Stress-triggered dysfunctions of microglia have been identified as a commonly...Dear Editor,Major depressive disorder(MDD)is one of the most common psychiatric illnesses that significantly increase the risk of suicide.1 Stress-triggered dysfunctions of microglia have been identified as a commonly occurred pathological feature of MDD.1–3 Microglial dysfunction contributes to the pathogenesis of MDD via immunoresponses/neuroinflammation-mediated neural damage and pathological synapse loss-mediated neural circuit disruption.1 Although the involvement of microglia in MDD has been widely investigated,the molecular mechanisms underlying microglial dysfunction remain largely unknown.Recently,we identified glutaminase 1(Gls1)as one key protein that participates in microglial dysfunction.4–6 Gls1 catalyzes the hydrolysis of glutamine to produce glutamate in the brain.4 Besides its well-known role in excitatory neurotoxicity,we found Gls1 up-regulation in microglia in animal models of Alzheimer’s disease and ischemic stroke.4,7 Gls1 activates microglia to overproduce cytokines and release inflammatory extracellular vesicles,therefore leading to neuroinflammation in animal models of Alzheimer’s disease and ischemic stroke.4–6 More importantly,Gls1 has been found to be up-regulated in the brains of MDD patients,and microglial Gls1 deficiency mitigated LPS-induced depression-like behaviors.8 However,LPS exposure is not an appropriate model to mimic MDD phenotypes,leaving the involvement of Gls1 in MDD an undetermined question.展开更多
Previous studies have reported that nearly one-fourth of coronavirus disease 2019(COVID-19)survivors suf-fer from persistent cognitive impairment,including impaired memory,attention,concentration,executive function,an...Previous studies have reported that nearly one-fourth of coronavirus disease 2019(COVID-19)survivors suf-fer from persistent cognitive impairment,including impaired memory,attention,concentration,executive function,and speed of information processing[1-3].Omicron is the latest severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant of concern(VOC)reported in November 2021[4],characterized by a large number of spike mutations,great transmissibility in the presence of other VOCs,and an ability to spread in populations with high level of immunity[4].However,whether patients infected with Omicron COVID-19 variant develop cognitive impairment,similar to those infected with other VOCs,remains unclear.展开更多
Pulmonary hypertension （PH）, as a complication of bronchiectasis, is associated with increased mortality. However, hemodynamic characteristics and the efficacy of pulmonary arterial hypertension （PAH） therapies in...Pulmonary hypertension （PH）, as a complication of bronchiectasis, is associated with increased mortality. However, hemodynamic characteristics and the efficacy of pulmonary arterial hypertension （PAH） therapies in patients with bronchiectasis and PH remain unknown. Patients with bilateral bronchiectasis and concurrent PH were included in the study. Patient characteristics at baseline and during follow-up, as well as survival, were analyzed. This observational study was conducted in 36 patients with a mean age of 51.5 years （range, 17-74 years）. The 6 min walking distance was 300.8 ± 93.3 m. The mean pulmonary arterial pressure （PAP） was 41.5 ± 11.7 mmHg, cardiac output was 5.2 ± 1.4 L/min, and pulmonary vascular resistance was 561.5 ± 281.5 dyn.s.cm-5. The mean PAP was 〉 35 mmHg in 75% of the cases. Mean PAP was inversely correlated with arterial oxygen saturation values （r = -0.45, P = 0.02）. In 24 patients who received oral PAH therapy, systolic PAP was reduced from 82.4 ±27.0 mmHg to 65.5 ± 20.9 mmHg （P = 0.025） on echocardiography after a median of 6 months of follow-up. The overall probability of survival was 97.1% at 1 year, 83.4% at 3 years, and 64.5% at 5 years. Given the results, we conclude that PH with severe hemodynamic impairment can occur in patients with bilateral bronchiectasis, and PAH therapy might improve hemodynamics in such patients. Prospective clinical trials focusing on this patient population are warranted.展开更多
Pulmonary hypertension(PH)is featured by pulmonary vascular and cardiac remodeling.Rehabilitation exercise can improve patients’quality of life.We previously pinpointed a potential glutamine metabolism dysfunction in...Pulmonary hypertension(PH)is featured by pulmonary vascular and cardiac remodeling.Rehabilitation exercise can improve patients’quality of life.We previously pinpointed a potential glutamine metabolism dysfunction in PH.Hence,we aim to investigate whether rehabilitation exercise could mitigate right ventricular and pulmonary vascular remodeling and its effect on glutaminase(GLS).We collected clinical indicators of PH patients and analyzed their correlation with GLS.Rehabilitation exercise(moderate intensity swimming exercise)was performed in monocrotaline-induced PH(MCT-PH)rats.We found that plasma GLS1 level in patients was lower than healthy subjects,and it was negatively correlated with end-systolic stage eccentricity index,right atrial transverse dimension and right atrial longitudinal dimension.MCT-PH rats displayed pulmonary vascular remodeling and right ventricular hypertrophy.Compared to control rats,higher levels of GLS1 and GLS2 mRNA in lung and lower levels of these two isoforms of GLS in right ventricle(RV)were displayed in MCT-PH rats.After swimming exercise,GLS mRNA levels in the lung and RV were significantly upregulated,and the cross-sectional area of right ventricular cardiomyocytes was significantly decreased although the percentage of pulmonary arteriolar medial wall thickness was not significantly changed.Therefore,we hold the opinion that plasma GLS1 level was decreased in PH.The transcriptional levels of GLS1 and GLS2 were increased in the lung tissues in PH,but were decreased in the RV tissues.Meanwhile,the changes of GLS levels indicated the pulmonary vascular and right ventricular remodeling.Whereas moderate intensity swimming exercise might improve the right ventricular remodeling by regulating the levels of GLS.展开更多
基金Program of Fundamental Research Funds for the Central Universities,Grant/Award Number:22120220562Program of Natural Science Foundation of Shanghai,Grant/Award Number:201409004100 and 21ZR1453800+1 种基金Three Year Action Plan to Promote Clinical Skills and Clinical Innovation in Municipal Hospitals,Grant/Award Number:SHDC2020CR6016-002 and SHDC2020CR4021Program of Shanghai Pulmonary Hospital,Grant/Award Number:fkzr2320 and FKLY20005。
文摘Pericytes are the main cellular components of tiny arteries and capillaries.Studies have found that pericytes can undergo morphological contraction or relaxation under stimulation by cytokines,thus affecting the contraction and relaxation of microvessels and playing an essential role in regulating vascular microcirculation.Moreover,due to the characteristics of stem cells,pericytes can differentiate into a variety of inflammatory cell phenotypes,which then affect the immune function.Additionally,pericytes can also participate in angiogenesis and wound healing by interacting with endothelial cells in vascular microcirculation disorders.Here we review the origin,biological phenotype and function of pericytes,and discuss the potential mechanisms of pericytes in vascular microcirculation disorders,especially in pulmonary hypertension,so as to provide a sound basis and direction for the prevention and treatment of vascular microcirculation diseases.
基金Central University Basic Research Fund of China,Grant/Award Number:22120220562National Natural Science Foundation of China,Grant/Award Number:81870044+1 种基金Natural Science Foundation of Shanghai,Grant/Award Number:201409004100 and 21ZR1453800Shanghai Pulmonary Hospital,Grant/Award Number:FKLY20005 and fkzr2320。
文摘Background:Circular RNAs(circRNAs)have been recognized as significant regulators of pulmonary hypertension(PH);however,the differential expression and function of circRNAs in different vascular cells under hypoxia remain unknown.Here,we identified co-differentially expressed circRNAs and determined their putative roles in the proliferation of pulmonary artery smooth muscle cells(PASMCs),pulmonary microvascular endothelial cells(PMECs),and pericytes(PCs)under hypoxia.Methods:Whole transcriptome sequencing was performed to analyze the differential expression of circRNAs in three different vascular cell types.Bioinformatic analysis was used to predict their putative biological function.Quantitative real-time polymerase chain reaction,Cell Counting Kit-8,and EdU Cell Proliferation assays were carried out to determine the role of circular postmeiotic segregation 1(circPMS1)as well as its potential sponge mechanism in PASMCs,PMECs,and PCs.Results:PASMCs,PMECs,and PCs exhibited 16,99,and 31 differentially expressed circRNAs under hypoxia,respectively.CircPMS1 was upregulated in PASMCs,PMECs,and PCs under hypoxia and enhanced the proliferation of vascular cells.CircPMS1may upregulate DEP domain containing 1(DEPDC1)and RNA polymerase II subunit D expression by targeting microRNA-432-5p(miR-432-5p)in PASMCs,upregulate MAX interactor 1(MXI1)expression by targeting miR-433-3p in PMECs,and upregulate zinc finger AN1-type containing 5(ZFAND5)expression by targeting miR-3613-5p in PCs.Conclusions:Our results suggest that circPMS1 promotes cell proliferation through the miR-432-5p/DEPDC1 or miR-432-5p/POL2D axis in PASMCs,through the miR-433-3p/MXI1 axis in PMECs,and through the miR-3613-5p/ZFAND5 axis in PCs,which provides putative targets for the early diagnosis and treatment of PH.
基金Program of Natural Science Foundation of Shanghai,Grant/Award Number:21ZR1453800 and 22ZR1452400Program of National Natural Science Foundation of China,Grant/Award Number:82370057+3 种基金Fundamental Research Funds for the Central Universities,Grant/Award Number:22120220562Program of Shanghai Municipal Health Commission,Grant/Award Number:20204Y0384Program of National Key Research and Development Project of China,Grant/Award Number:2023YFC2509500。
文摘Background:Our previous study found that mouse embryonic neural stem cell(NSC)-derived exosomes(EXOs)regulated NSC differentiation via the miR-9/Hes1 axis.However,the effects of EXOs on brain microvascular endothelial cell(BMEC)dysfunction via the miR-9/Hes1 axis remain unknown.Therefore,the current study aimed to determine the effects of EXOs on BMEC proliferation,migration,and death via the miR-9/Hes1 axis.Methods:Immunofluorescence,quantitative real-time polymerase chain reaction,cell counting kit-8 assay,wound healing assay,calcein-acetoxymethyl/propidium iodide staining,and hematoxylin and eosin staining were used to determine the role and mechanism of EXOs on BMECs.Results:EXOs promoted BMEC proliferation and migration and reduced cell death under hypoxic conditions.The overexpression of miR-9 promoted BMEC prolifera-tion and migration and reduced cell death under hypoxic conditions.Moreover,miR-9 downregulation inhibited BMEC proliferation and migration and also promoted cell death.Hes1 silencing ameliorated the effect of amtagomiR-9 on BMEC proliferation and migration and cell death.Hyperemic structures were observed in the regions of the hippocampus and cortex in hypoxia-induced mice.Meanwhile,EXO treatment improved cerebrovascular alterations.Conclusion:NSC-derived EXOs can promote BMEC proliferation and migra-tion and reduce cell death via the miR-9/Hes1 axis under hypoxic conditions.Therefore,EXO therapeutic strategies could be considered for hypoxia-induced vascular injury.
基金Program of the National Natural Science Foundation of China,Grant/Award Number:81700045,81870042 and 82200065The Department Development Fund of Shanghai Pulmonary Hospital,Grant/Award Number:201906-0314+2 种基金The Program of Shanghai Pulmonary Hospital,Grant/Award Number:FKLY20011The Three-year Action Plan to Promote Clinical Skills and Clinical Innovation in Municipal Hospitals,Grant/Award Number:SHDC2020CR4021Young Talent Program of Shanghai Municipal Health Commission,Grant/Award Number:2022YQ070。
文摘Background:The maintenance dosage of selexipag is categorized as low,medium or high.In order to assess the efficacy and safety of different dosages of selexipag for the risk stratification of pulmonary arterial hypertension(PAH),we performed a sys-tematic review and meta-analysis.Methods:Studies assessing PAH risk stratification indices,such as the World Health Organization functional class(WHO-FC),six-minute walk distance(6MWD),N-terminal pro-B-type natriuretic peptide(NT-proBNP)level,right atrial pressure(RAP),cardiac index(CI)and mixed venous oxygen saturation(SvO2),were included.Results:Thirteen studies were included.Selexipag led to improvements in the 6MWD(MD:24.20 m,95%CI:10.74-37.67),NT-proBNP(SMD:-0.41,95%CI:-0.79-0.04),CI(MD:0.47 L/min/m^(2),95%CI:0.17-0.77)and WHO-FC(OR:0.564,95%CI:0.457-0.697).Subgroup analysis demonstrated that all three dosages improved the 6MWD.A moderate dosage led to improvements in the CI(MD:0.30 L/min/m^(2),95%CI:0.15-0.46)and WHO-FC(OR:0.589,95%CI:0.376-0.922).Within 6 months of treatment,only the WHO-FC and CI were significantly improved(OR:0.614,95%CI:0.380-0.993;MD:0.30 L/min/m^(2),95%CI:0.16-0.45,respectively).More than 6 months of treatment significantly improved the 6MWD,WHO-FC and NT-proBNP(MD:40.87 m,95%CI:10.97-70.77;OR:0.557,95%CI:0.440-0.705;SMD:-0.61,95%CI:-1.17-0.05,respectively).Conclusions:Low,medium,and high dosages of selexipag all exhibited good effects.When treatment lasted for more than 6 months,selexipag exerted obvious effects,even in the low-dosage group.This finding is important for guiding individualized treatments.
基金supported by the Program of National Natural Science Foundation of China (81870042 and 81900050)Program of Natural Science Foundation of Shanghai (21ZR1453800)Program of Shanghai Pulmonary Hospital (FKLY20005)
文摘Circular RNAs(circRNAs)are endogenous RNAs with a covalently closed single-stranded transcript.They are a novel class of genomic regulators that are linked to many important development and disease processes and are being pursued as clinical and therapeutic targets.Using the most powerful RNA sequencing and bioinformatics techniques,a large number of circRNAs have been identified and further functional studies have been performed.It is known that circRNAs act as potential biomarkers,sponges for microRNAs(miRNAs)and RNA-binding proteins(RBPs),and regulators of mRNA transcription.They also participate in the translation of peptides or proteins.Many types of circRNAs are dysregulated in plasma or lung tissues,and they may be involved in regulating the proliferation and apoptosis of pulmonary artery endothelial cells(PAECs)and pulmonary artery smooth muscle cells(PASMCs),leading to pulmonary vascular remodeling in pulmonary hypertension(PH).One possible mechanism is that circRNAs can regulate the function of PAECs and PASMCs by acting as miRNA sponge.However,other potential mechanisms of action of circRNAs are still being actively explored in PH.This paper presents a systematic review of the biogenesis,biological characterization,relevant underlying functions,and future perspectives for studies of circRNAs in the pathogenesis of PH.
基金National Natural Science Foundation of China,Grant/Award Number:81700045,81870042 and 81900050Natural Science Foundation of Shanghai,Grant/Award Number:22ZR1452400+1 种基金Shanghai Municipal Commission of Health,Grant/Award Number:20204Y0384Shanghai Pulmonary Hospital,Grant/Award Number:fk18003 and fkyq1605。
文摘Prolactin(PRL)is a polypeptide hormone that is mainly synthesized and secreted by the lactotroph cells of the pituitary.There are two main isoforms of PRL:23-kDa PRL(named full-l ength PRL)and vasoinhibins(including 5.6–18 kDa fragments).Both act as circulating hormones and cytokines to stimulate or inhibit vascular formation at different stages and neovascularization,including endothelial cell proliferation and migration,protease production,and apoptosis.However,their effects on vascular function and cardiovascular diseases are different or even contrary.In addition to the structure,secretion regulation,and signal transduction of PRL/vasoinhibins,this review focuses on the pathological mechanism and clinical significance of PRL/vasoinhibins in cardiovascular diseases.
基金National Natural Science Foundation of China,Grant/Award Number:8 1870042Natural Science Foundation of Shanghai,Grant/Award Number:21ZR1453800。
文摘Background:Aberrant expression of microRNAs(miRNAs)has been associated with the pathogenesis of pulmonary hypertension(PH).It is,however,not clear whether miRNAs are involved in estrogen rescue of PH.Methods:Fresh plasma samples were prepared from 12 idiopathic pulmonary arterial hypertension(IPAH)patients and 12 healthy controls undergoing right heart cath-eterization in Shanghai Pulmonary Hospital.From each sample,5μg of total RNA was tagged and hybridized on microRNA microarray chips.Monocrotaline-induced PH(MCT-PH)male rats were treated with 17β-estradiol(E_(2))or vehicle.Subgroups were cotreated with estrogen receptor(ER)antagonist or with antagonist of miRNA.Results:Many circulating miRNAs,including miR-21-5p and miR-574-5p,were mark-edly expressed in patients and of interest in predicting mean pulmonary arterial pres-sure elevation in patients.The expression of miR-21-5p in the lungs was significantly upregulated in MCT-PH rats compared with the controls.However,miR-574-5p showed no difference in the lungs of MCT-PH rats and controls.miR-21-5p was se-lected for further analysis in rats as E_(2) strongly regulated it.E_(2) decreased miR-21-5p expression in the lungs of MCT-PH rats by ERβ.E_(2) reversed miR-21-5p target gene FilGAP downregulation in the lungs of MCT-PH rats.The abnormal expression of RhoA,ROCK2,Rac1 and c-Jun in the lungs of MCT-PH rats was inhibited by E_(2) and miR-21-5p antagonist.Conclusions:miR-21-5p level was remarkably associated with PH severity in patients.Moreover,the miR-21-5p/FilGAP signaling pathway modulated the protective effect of E_(2) on MCT-PH through ERβ.
基金National Natural Science Foundation of China,Grant/Award Number:81700045 and 82000059Program of Shanghai Pulmonary Hospital,Grant/Award Number:FKLY20005Three-year Action Plan to Promote Clinical Skills and Clinical Innovation in Municipal Hospitals,Grant/Award Number:SHDC2020CR4021。
文摘The association between blood eosinophil(EOS)counts and arterial/venous throm-bosis is unclear.We aim to explore whether EOS count is a risk factor for throm-bosis.We searched several databases and preprint platforms using core terms‘eosinophil’,‘myocardial infarction’,‘ischemic stroke’,and‘venous thromboembo-lism’(VTE),among others.Studies comparing the odds ratios(ORs)or risk ratios(RRs)of EOSs with the abovementioned diseases were eligible.Overall,22 studies were included.A high EOS count was associated with acute coronary artery throm-bosis events(OR:1.23,95%CI:1.15-1.32),short-term cerebral infarction and mor-tality(RR:2.87,95%CI:1.49-5.51).The short-term risk of VTE was more common in patients with EOS-related diseases(RR:6.52,95%CI:2.42-17.54).For coronary artery disease,a high EOS count was a protective factor against 6-month to 1-year mortality(RR:0.56,95%CI:0.45-0.69)but was associated with long-term mortal-ity(RR:1.64,95%CI:1.25-2.14).Therefore,we conclude that for coronary artery thrombosis,EOS count is not associated with AMI events in general population.It may be associated with NSTEMI and STEMI in CAD patients,but more studies are needed to confirm this.In addition,EOS count is associated with an increased risk of both short-and long-term mortality but is not predictive of the composite end-points.For cerebral artery thrombosis,EOS count may be associated with cerebral infarction and could lead to an increased risk of poor short-term prognosis.For VTEs,EOS count was a risk factor for some patients,especially those with acute-phase EOS-related diseases.
基金This work was supported by National Natural Science Foundation of China(81630003,82170058)Science Foundation for Outstanding Young Scholars of Henan Province(212300410027)+1 种基金Key Research Project of Ningxia Hui Autonomous Region(2019BFG02027)Project for College of Traditional Chinese Medicine of Henan University(No.2021YJYJZ07).
文摘Objective/Background:Proliferation is a widely recognized trigger for pulmonary hypertension(PH),a life-threatening,progressive disorder of pulmonary blood vessels.This study was aimed to identify some proliferation associated genes/targets for better comprehension of PH pathogenesis.Methods:Human pulmonary arterial smooth muscle cells(hPASMCs)were cultured in the presence or absence of human recombinant platelet derived growth factor(rhPDGF)-BB.Cells were collected for metabolomics or transcriptomics study.Gene profiling of lungs of PH rats after hypoxia exposure or of PH patients were retrieved from GEO database.Results:90 metabolites(VIP score>1,fold change>2 or<0.5 and p<.05)and 2701 unique metabolism associated genes(MAGs)were identified in rhPDGF-BB treated hPASMCs compared to control cells.In addition,1151 differentially expressed genes(313 upregulated and 838 downregulated)were identified in rhPDGF-BB treated hPASMCs compared to control cells(fold change>2 or<0.5 and p<.05).152 differentially expressed MAGs were then determined,out of which 9 hub genes(IL6,CXCL8,CCL2,CXCR4,CCND1,PLAUR,PLAU,HBEGF and F3)were defined as core proliferation associated hub genes in protein proten interaction analysis.In addition,the hub gene-based LASSO model can predict the occurrence of PH(AUC=0.88).The expression of CXCR4,as one of the hub genes,was positively correlated to immune cell infiltrates.Conclusion:Our findings revealed some key proliferation associated genes in PH,which provide the crucial information concerning complex metabolic reprogramming and inflammatory modulation in response to proliferation signals and might offer therapeutic gains for PH.
基金supported by the grants from the program of Shanghai Hospital Development Center(No.SHDC2020CR6016-002)the Program of National Key Research and Development Project of China(No.2023YFC2509500)+2 种基金the Program of Natural Science Foundation of Shanghai(No.22ZR1452400)the Pujiang Talent Program(No.22PJD064)the Program of Shanghai Pulmonary Hospital(Nos.FK18003 and FKLY20005)
文摘To the Editor:Obesity,which has currently become an important public health problem,has been considered a positive prognostic factor for patients with multiple chronic disorders,including pulmonary arterial hypertension,a phenomenon known as the“obesity paradox”.[1]However,whether this phenomenon exists in pulmonary hypertension(PH)secondary to chronic lung disease(CLD-PH)remains unknown.This study aimed to elucidate the association between body mass index(BMI)and mortality in CLD-PH patients.
基金supported in part by research grants from the National Natural Science Foundation of China(Nos.91949204 and 81830037 to J.C.Z.,Nos.81971145 and 82271477 to X.X.)Independent Original Basic Research Program of Tongji University(No.22120220596 to X.X.).
文摘Dear Editor,Major depressive disorder(MDD)is one of the most common psychiatric illnesses that significantly increase the risk of suicide.1 Stress-triggered dysfunctions of microglia have been identified as a commonly occurred pathological feature of MDD.1–3 Microglial dysfunction contributes to the pathogenesis of MDD via immunoresponses/neuroinflammation-mediated neural damage and pathological synapse loss-mediated neural circuit disruption.1 Although the involvement of microglia in MDD has been widely investigated,the molecular mechanisms underlying microglial dysfunction remain largely unknown.Recently,we identified glutaminase 1(Gls1)as one key protein that participates in microglial dysfunction.4–6 Gls1 catalyzes the hydrolysis of glutamine to produce glutamate in the brain.4 Besides its well-known role in excitatory neurotoxicity,we found Gls1 up-regulation in microglia in animal models of Alzheimer’s disease and ischemic stroke.4,7 Gls1 activates microglia to overproduce cytokines and release inflammatory extracellular vesicles,therefore leading to neuroinflammation in animal models of Alzheimer’s disease and ischemic stroke.4–6 More importantly,Gls1 has been found to be up-regulated in the brains of MDD patients,and microglial Gls1 deficiency mitigated LPS-induced depression-like behaviors.8 However,LPS exposure is not an appropriate model to mimic MDD phenotypes,leaving the involvement of Gls1 in MDD an undetermined question.
基金supported by the National Natural Science Foundation of China(91949204 and 81830037 to J.C.Z.,81971145 and 82271477 to X.X.,81730032 to L.X.,81870042 to P.Y.)the Natural Science Foundation of Shanghai(21ZR1453800 to P.Y.).
文摘Previous studies have reported that nearly one-fourth of coronavirus disease 2019(COVID-19)survivors suf-fer from persistent cognitive impairment,including impaired memory,attention,concentration,executive function,and speed of information processing[1-3].Omicron is the latest severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant of concern(VOC)reported in November 2021[4],characterized by a large number of spike mutations,great transmissibility in the presence of other VOCs,and an ability to spread in populations with high level of immunity[4].However,whether patients infected with Omicron COVID-19 variant develop cognitive impairment,similar to those infected with other VOCs,remains unclear.
文摘Pulmonary hypertension （PH）, as a complication of bronchiectasis, is associated with increased mortality. However, hemodynamic characteristics and the efficacy of pulmonary arterial hypertension （PAH） therapies in patients with bronchiectasis and PH remain unknown. Patients with bilateral bronchiectasis and concurrent PH were included in the study. Patient characteristics at baseline and during follow-up, as well as survival, were analyzed. This observational study was conducted in 36 patients with a mean age of 51.5 years （range, 17-74 years）. The 6 min walking distance was 300.8 ± 93.3 m. The mean pulmonary arterial pressure （PAP） was 41.5 ± 11.7 mmHg, cardiac output was 5.2 ± 1.4 L/min, and pulmonary vascular resistance was 561.5 ± 281.5 dyn.s.cm-5. The mean PAP was 〉 35 mmHg in 75% of the cases. Mean PAP was inversely correlated with arterial oxygen saturation values （r = -0.45, P = 0.02）. In 24 patients who received oral PAH therapy, systolic PAP was reduced from 82.4 ±27.0 mmHg to 65.5 ± 20.9 mmHg （P = 0.025） on echocardiography after a median of 6 months of follow-up. The overall probability of survival was 97.1% at 1 year, 83.4% at 3 years, and 64.5% at 5 years. Given the results, we conclude that PH with severe hemodynamic impairment can occur in patients with bilateral bronchiectasis, and PAH therapy might improve hemodynamics in such patients. Prospective clinical trials focusing on this patient population are warranted.
基金The work was supported by the Program of National Natural Science Foundation of China(81,700,045,82,000,059)the Three-year Action Plan to Promote Clinical Skills and Clinical Innovation in Municipal Hospitals(SHDC2020CR4021)the Program of Shanghai Pulmonary Hospital(FKLY20005).
文摘Pulmonary hypertension(PH)is featured by pulmonary vascular and cardiac remodeling.Rehabilitation exercise can improve patients’quality of life.We previously pinpointed a potential glutamine metabolism dysfunction in PH.Hence,we aim to investigate whether rehabilitation exercise could mitigate right ventricular and pulmonary vascular remodeling and its effect on glutaminase(GLS).We collected clinical indicators of PH patients and analyzed their correlation with GLS.Rehabilitation exercise(moderate intensity swimming exercise)was performed in monocrotaline-induced PH(MCT-PH)rats.We found that plasma GLS1 level in patients was lower than healthy subjects,and it was negatively correlated with end-systolic stage eccentricity index,right atrial transverse dimension and right atrial longitudinal dimension.MCT-PH rats displayed pulmonary vascular remodeling and right ventricular hypertrophy.Compared to control rats,higher levels of GLS1 and GLS2 mRNA in lung and lower levels of these two isoforms of GLS in right ventricle(RV)were displayed in MCT-PH rats.After swimming exercise,GLS mRNA levels in the lung and RV were significantly upregulated,and the cross-sectional area of right ventricular cardiomyocytes was significantly decreased although the percentage of pulmonary arteriolar medial wall thickness was not significantly changed.Therefore,we hold the opinion that plasma GLS1 level was decreased in PH.The transcriptional levels of GLS1 and GLS2 were increased in the lung tissues in PH,but were decreased in the RV tissues.Meanwhile,the changes of GLS levels indicated the pulmonary vascular and right ventricular remodeling.Whereas moderate intensity swimming exercise might improve the right ventricular remodeling by regulating the levels of GLS.
