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 ...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 fibroblastselective 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.展开更多
目的探讨泛素特异性蛋白酶10(ubiquitin-specifi c protease 10,USP10)蛋白及其m RNA在人弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)与淋巴结反应性增生(reactive lymph node hyperplasia,RLH)中的表达及其临床意义。方...目的探讨泛素特异性蛋白酶10(ubiquitin-specifi c protease 10,USP10)蛋白及其m RNA在人弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)与淋巴结反应性增生(reactive lymph node hyperplasia,RLH)中的表达及其临床意义。方法选取70例人DLBCL及70例RLH组织,采用组织芯片和免疫组织化学染色检测USP10的蛋白表达,分析其与DLBCL分子亚型及DLBCL预后相关分子之间的关系,并采用GEO数据库分析USP10 m RNA表达水平。结果 USP10在DLBCL组织中的阳性表达率显著高于RLH组织的B淋巴细胞,在非生发中心亚型(non-germinal center B-cell-like type,nonGCB)DLBCL组织中的阳性表达率明显高于生发中心亚型(germinal center B-cell-like type,GCB)DLBCL组织;Spearman等级相关分析显示,USP10与DLBCL预后相关分子中的CD5、Bcl-2蛋白表达呈正相关,而与p53,c-Myc及Ki67蛋白表达无相关性;USP10 m RNA在DLBCL组织及RLH组织中的表达差异。结论 USP10在DLBCL组织中的表达明显增加,尤其是在预后较差的non-GCB亚型或CD5阳性或无Bcl-2阳性的DLBCL中,表明该蛋白是DLBCL患者预后不良的分子标记物之一。展开更多
基金supported by grants from the National Key R&D Program of China (2018YFC1311300)the Key Project of the National Natural Science Foundation of China (No. 81530012)+3 种基金the National Natural Science Foundation of China (Nos. 81860080, 82170245 and 81700254)the Fundamental Research Funds for the Central Universities (2042018kf1032, China)the Development Center for Medical Science and Technology National Health and Family Planning Commission of the People’s Republic of China (The prevention and control project of cardiovascular disease, 2016ZX008-01)Science and Technology Planning Projects of Wuhan (2018061005132295)
文摘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 fibroblastselective 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.
文摘目的探讨泛素特异性蛋白酶10(ubiquitin-specifi c protease 10,USP10)蛋白及其m RNA在人弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)与淋巴结反应性增生(reactive lymph node hyperplasia,RLH)中的表达及其临床意义。方法选取70例人DLBCL及70例RLH组织,采用组织芯片和免疫组织化学染色检测USP10的蛋白表达,分析其与DLBCL分子亚型及DLBCL预后相关分子之间的关系,并采用GEO数据库分析USP10 m RNA表达水平。结果 USP10在DLBCL组织中的阳性表达率显著高于RLH组织的B淋巴细胞,在非生发中心亚型(non-germinal center B-cell-like type,nonGCB)DLBCL组织中的阳性表达率明显高于生发中心亚型(germinal center B-cell-like type,GCB)DLBCL组织;Spearman等级相关分析显示,USP10与DLBCL预后相关分子中的CD5、Bcl-2蛋白表达呈正相关,而与p53,c-Myc及Ki67蛋白表达无相关性;USP10 m RNA在DLBCL组织及RLH组织中的表达差异。结论 USP10在DLBCL组织中的表达明显增加,尤其是在预后较差的non-GCB亚型或CD5阳性或无Bcl-2阳性的DLBCL中,表明该蛋白是DLBCL患者预后不良的分子标记物之一。
