The journal of cardiovascular aging最新文献

Obesity is associated with chronic inflammation in adipose tissue (AT), mainly evidenced by infiltration and phenotypic changes of various types of immune cells. Macrophages are the major innate immune cells and represent the predominant immune cell population within AT. Lymphocytes, including T cells and B cells, are adaptive immune cells and constitute another important immune cell population in AT. In obesity, CD8+ effector memory T cells, CD4+ Th1 cells, and B2 cells are increased in AT and promote AT inflammation, while regulatory T cells and Th2 cells, which usually function as immune regulatory or type 2 inflammatory cells, are reduced in AT. Immune cells may regulate the metabolism of adipocytes and other cells through various mechanisms, contributing to the development of metabolic diseases, including insulin resistance and type 2 diabetes. Efforts targeting immune cells and inflammation to prevent and treat obesity-linked metabolic disease have been explored, but have not yielded significant success in clinical studies. This review provides a concise overview of the changes in lymphocyte populations within AT and their potential role in AT inflammation and the regulation of metabolic functions in the context of obesity.

Acetyltransferases are enzymes that catalyze the transfer of an acetyl group to a substrate, a modification referred to as acetylation. Loss-of-function variants in genes encoding acetyltransferases can lead to congenital disorders, often characterized by intellectual disability and heart and muscle defects. Their activity is influenced by dietary nutrients that alter acetyl coenzyme A levels, a key cofactor. Cardiovascular diseases, including ischemic, hypertensive, and diabetic heart diseases - leading causes of mortality in the elderly - are largely attributed to prolonged lifespan and the growing prevalence of metabolic syndrome. Acetyltransferases thus serve as a crucial link between lifestyle modifications, cardiometabolic disease, and aging through both epigenomic and non-epigenomic mechanisms. In this review, we discuss the roles and relevance of acetyltransferases. While the sirtuin family of deacetylases has been extensively studied in longevity, particularly through fasting-mediated NAD⁺ metabolism, recent research has brought attention to the essential roles of acetyltransferases in health and aging-related pathways, including cell proliferation, DNA damage response, mitochondrial function, inflammation, and senescence. We begin with an overview of acetyltransferases, classifying them by domain structure, including canonical and non-canonical lysine acetyltransferases, N-terminal acetyltransferases, and sialic acid O-acetyltransferases. We then discuss recent advances in understanding acetyltransferase-related pathologies, particularly focusing on cardiovascular disease and aging, and explore their potential therapeutic applications for promoting health in older individuals.

Introduction: Gradual exposure to a chronic hypoxic environment leads to cardiomyocyte proliferation and improved cardiac function in mouse models through a reduction in oxidative DNA damage. However, the upstream transcriptional events that link chronic hypoxia to DNA damage have remained obscure.

Aim: We sought to determine whether hypoxia signaling mediated by the hypoxia-inducible factor 1 or 2 (HIF1A or HIF2A) underlies the proliferation phenotype that is induced by chronic hypoxia.

Methods and results: We used genetic loss-of-function models using cardiomyocyte-specific HIF1A and HIF2A gene deletions in chronic hypoxia. We additionally characterized a cardiomyocyte-specific HIF2A overexpression mouse model in normoxia during aging and upon injury. We performed transcriptional profiling with RNA-sequencing on cardiac tissue, from which we verified candidates at the protein level. We find that HIF2A - rather than HIF1A - mediates hypoxia-induced cardiomyocyte proliferation. Ectopic, oxygen-insensitive HIF2A expression in cardiomyocytes reveals the cell-autonomous role of HIF2A in cardiomyocyte proliferation. HIF2A overexpression in cardiomyocytes elicits cardiac regeneration and improvement in systolic function after myocardial infarction in adult mice. RNA-sequencing reveals that ectopic HIF2A expression attenuates DNA damage pathways, which was confirmed with immunoblot and immunofluorescence.

Conclusion: Our study provides mechanistic insights about a new approach to induce cardiomyocyte renewal and mitigate cardiac injury in the adult mammalian heart. In light of evidence that DNA damage accrues in cardiomyocytes with aging, these findings may help to usher in a new therapeutic approach to overcome such age-related changes and achieve regeneration.