Metabolic landscape in cardiac aging:insights into molecular biology and therapeutic implications

Cardiac aging is evident by a reduction in function which subsequently contributes to heart failure.The metabolic microenvironment has been identified as a hallmark of malignancy,but recent studies have shed light on its role in cardiovascular diseases(CVDs).Various metabolic pathways in cardiomyocytes and noncardiomyocytes determine cellular senescence in the aging heart.Metabolic alteration is a common process throughout cardiac degeneration.Importantly,the involvement of cellular senescence in cardiac injuries,including heart failure and myocardial ischemia and infarction,has been reported.However,metabolic complexity among human aging hearts hinders the development of strategies that targets metabolic susceptibility.Advances over the past decade have linked cellular senescence and function with their metabolic reprogramming pathway in cardiac aging,including autophagy,oxidative stress,epigenetic modifications,chronic inflammation,and myocyte systolic phenotype regulation.In addition,metabolic status is involved in crucial aspects of myocardial biology,from fibrosis to hypertrophy and chronic inflammation.However,further elucidation of the metabolism involvement in cardiac degeneration is still needed.Thus,deciphering the mechanisms underlying how metabolic reprogramming impacts cardiac aging is thought to contribute to the novel interventions to protect or even restore cardiac function in aging hearts.Here,we summarize emerging concepts about metabolic landscapes of cardiac aging,with specific focuses on why metabolic profile alters during cardiac degeneration and how we could utilize the current knowledge to improve the management of cardiac aging.

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

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.