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

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 · 发表于：Acta Pharmaceutica Sinica B · 年份：2022 · DOI：10.1016/j.apsb.2022.07.022 · 被引用次数：58 · 研究领域：Cardiac Fibrosis and Remodeling、Cardiovascular Function and Risk Factors、Cardiac Ischemia and Reperfusion

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 TGF β 1–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, b...