Cardiac fibroblast heat shock protein 47 aggravates cardiac fibrosis post myocardial ischemia–reperfusion injury by encouraging ubiquitin specific peptidase 10 dependent Smad4 deubiquitination

心脏纤维化 泛素 热休克蛋白 医学 再灌注损伤 纤维化 缺血 心肌缺血 成纤维细胞 心脏功能不全 心脏病学 内科学 化学 细胞生物学 生物 心力衰竭 基因 体外 生物化学
作者
Saiyang Xie,Yun Xing,Wenke Shi,Min Zhang,Mengya Chen,Wenxi Fang,Shiqiang Liu,Tong Zhang,Xiaofeng Zeng,Si Chen,Shasha Wang,Wei Deng,Qi‐Zhu Tang
出处
期刊:Acta Pharmaceutica Sinica B [Elsevier]
卷期号:12 (11): 4138-4153 被引量:19
标识
DOI:10.1016/j.apsb.2022.07.022
摘要

Despite complications were significantly reduced due to the popularity of percutaneous coronary 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 remodeling 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 deubiquitination by recruiting ubiquitin-specific peptidase 10 (USP10) in fibroblasts. However, cardiac fibroblast specific USP10 deficiency abolished HSP47-mediated fibrogenesis in hearts. Moreover, blockage of HSP47 with Col003 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.
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