SIRT6 in Vascular Diseases, from Bench to Bedside

Abstract

Aging is a key risk factor for angiogenic dysfunction and cardiovascular diseases, including heart failure, hypertension, atherosclerosis, diabetes, and stroke. Members of the NAD + -dependent class III histone deacetylase family, sirtuins, are conserved regulators of aging and cardiovascular and cerebrovascular diseases. The sirtuin SIRT6 is predominantly located in the nucleus and shows deacetylase activity for acetylated histone 3 lysine 56 and lysine 9 as well as for some non-histone proteins. Over the past decade, experimental analyses in rodents and non-human primates have demonstrated the critical role of SIRT6 in extending lifespan. Recent studies highlighted the pleiotropic protective actions of SIRT6 in angiogenesis and cardiovascular diseases, including atherosclerosis, hypertension, heart failure, and stroke. Mechanistically, SIRT6 participates in vascular diseases via epigenetic regulation of endothelial cells, vascular smooth muscle cells, and immune cells. Importantly, SIRT6 activators (e.g., MDL-800/MDL-811) have provided therapeutic value for treating age-related vascular disorders. Here, we summarized the roles of sirtuins in cardiovascular diseases; reviewed recent advances in the understanding of SIRT6 in vascular biology, cardiovascular aging, and diseases; highlighted its therapeutic potential; and discussed future perspectives.

Helpful to Live Healthier? Intermittent Hypoxic/Ischemic Training Benefits Vascular Homeostasis and Lipid Metabolism with Activating SIRT1 Pathways in Overweight/Obese Individuals

“…In the last decade, few studies on IHT have concentrated on its mechanisms or have simply discovered the elevated expression of HIF-1α and its downstream targets VEGF and NO [41,43] but not the interlocking relationship between lipid metabolism and vascular protection, where various biomarker factors and pathways may be involved. Considering SIRT1 works as a hypoxia-responsive energy sensor and plays a key epigenetic role in lipid homeostasis, metabolic regulation, and vascular endothelial function [44][45][46][47], we have noticed the multiple protective roles of SIRT1 in lipid metabolism and vascular homeostasis after analyzing the expression of relative metabolic biomarker proteins. SIRT1 is a class III nicotinamide-adenine-dinucleotide (NAD+)-dependent histone deacetylase (HDAC) that plays a crucial role in the maintenance of genome stability, apoptosis, autophagy, senescence, proliferation, and lifespan extension [48,49].…”

Downregulation of Sirt6 by CD38 promotes cell senescence and aging

“…Recent studies highlighted the pleiotropic protective AGING actions of Sirt6 in angiogenesis and cardiovascular diseases, including atherosclerosis, hypertension, heart failure and stroke. Mechanistically, Sirt6 participates in vascular diseases via epigenetic regulation of endothelial cells, vascular smooth muscle cells and immune cells [64]. Sirt6 has emerged as a promising target for the development of small-molecule activators and inhibitors possessing therapeutic potential in diseases ranging from cancer to age-related disorders [65][66][67].…”

Sirtuins in kidney diseases: potential mechanism and therapeutic targets

“…Deacetylation of histone H3K56 regulates β-catenin-related genes, represses transcription of fibre-related genes, and regulates renal interstitial fibrosis [ 53 ]. Sirt6 also deacetylates non-histone proteins in the nucleus and cytoplasm, including members of the FOXO family, p53, Smad, and NAMPT [ 54 ]. Sirt6 regulates renal interstitial fibrosis by deacetylating runt-related transcription factor 2 (Runx2), promotes Runx2 translocation out of the nucleus, mediates activation of the ubiquitin-protease system, causes degradation of Runx2, and inhibits vascular calcification in chronic kidney diseases (CKD) [ 55 ].…”