Despite complications were significantly reduced due to the popularity of percutaneous cor-onary intervention(PCI)in clinical trials,reperfusion injury and chronic cardiac remodeling significantly contribute to poor prognosis and rehabilitation in AMI patients.We revealed the effects of HSP47 on myocardial ischemia-reperfusion injury(IRI)and shed light on the underlying molecular mechanism.We generated adult mice with lentivirus-mediated or miRNA(mi1/133TS)-aided cardiac fibroblast-selective HSP47 overexpression.Myocardial IRI was induced by 45-min occlusion of the left anterior descending(LAD)artery followed by 24 h reperfusion in mice,while ischemia-mediated cardiac remo-deling was induced by four weeks of reperfusion.Also,the role of HSP47 in fibrogenesis was evaluated in cardiac fibroblasts following hypoxia-reoxygenation(HR).Extensive HSP47 was observed in murine infarcted hearts,human ischemic hearts,and cardiac fibroblasts and accelerated oxidative stress and apoptosis after myocardial IRI.Cardiac fibroblast-selective HSP47 overexpression exacerbated cardiac dysfunction caused by chronic myocardial IRI and presented deteriorative fibrosis and cell proliferation.HSP47 upregulation in cardiac fibroblasts promoted TGFβ1-Smad4 pathway activation and Smad4 deu-biquitination by recruiting ubiquitin-specific peptidase 10(USP10)in fibroblasts.However,cardiac fibro-blast specific USP10 deficiency abolished HSP47-mediated fibrogenesis in hearts.Moreover,blockage of HSP47 with Co1003 disturbed fibrogenesis in fibroblasts following HR.Altogether,cardiac fibroblast HSP47 aggravates fibrosis post-myocardial IRI by enhancing USP10-dependent Smad4 deubiquitination,which provided a potential strategy for myocardial IRI and cardiac remodeling.

Saiyang Xie;Yun Xing;Wenke Shi;Min Zhang;Mengya Chen;Wenxi Fang;Shiqiang Liu;Tong Zhang;Xiaofeng Zeng;Si Chen;Shasha Wang;Wei Deng;Qizhu Tang

Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan 430060,China;Hubei Key Laboratory of Metabolic and Chronic Diseases,Wuhan 430060,China;Cardiovascular Research Institute of Wuhan University,Wuhan 430060,China

药学学报（英文版）

[1]Saiyang Xie;Yun Xing;Wenke Shi;Min Zhang;Mengya Chen;Wenxi Fang;Shiqiang Liu;Tong Zhang;Xiaofeng Zeng;Si Chen;Shasha Wang;Wei Deng;Qizhu Tang-.Cardiac fibroblast heat shock protein 47 aggravates cardiac fibrosis post myocardial ischemia-reperfusion injury by encouraging ubiquitin specific peptidase 10 dependent Smad4 deubiquitination)[J].药学学报（英文版）,2022(11):4138-4153

mi1,133TS,deling,infarcted,deteriorative,biquitination,Co1003

Cardiac,heat,shock,protein,aggravates,cardiac,fibrosis,post,myocardial,ischemia,reperfusion,injury,by,encouraging,specific,peptidase,dependent,Smad4,deubiquitination,Despite,complications,were,significantly,reduced,due,popularity,percutaneous,cor,onary,intervention,PCI,clinical,trials,chronic,remodeling,contribute,poor,prognosis,rehabilitation,AMI,patients,We,revealed,effects,HSP47,IRI,light,underlying,molecular,mechanism,generated,adult,mice,lentivirus,mediated,miRNA,aided,selective,overexpression,Myocardial,was,induced,occlusion,left,anterior,descending,LAD,artery,followed,while,four,weeks,Also,role,fibrogenesis,evaluated,fibroblasts,following,hypoxia,reoxygenation,Extensive,observed,murine,hearts,human,ischemic,accelerated,oxidative,stress,apoptosis,after,exacerbated,dysfunction,caused,presented,cell,proliferation,upregulation,promoted,TGF,pathway,activation,recruiting,USP10,However,deficiency,abolished,Moreover,blockage,disturbed,Altogether,enhancing,which,provided,potential,strategy

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