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
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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