Sirtuin 6 deficiency induces endothelial cell senescence via downregulation of forkhead box M1 expression

Abstract

Cellular senescence of endothelial cells causes vascular dysfunction, promotes atherosclerosis, and contributesto the development of age-related vascular diseases. Sirtuin 6 (SIRT6), a conserved NAD+-dependent protein deacetylase, has beneficial effects against aging, despite the fact that its functional mechanisms are largely uncharacterized. Here, we show that SIRT6 protects endothelial cells from senescence. SIRT6 expression is progressively decreased during both oxidative stress-induced senescence and replicative senescence. SIRT6 deficiency leads to endothelial dysfunction, growth arrest, and premature senescence. Using genetically engineered endothelial cell-specific SIRT6 knockout mice, we also show that down-regulation of SIRT6 expression in endothelial cells exacerbates vascular aging. Expression microarray analysis demonstrated that SIRT6 modulates the expression of multiple genes involved in cell cycle regulation. Specifically, SIRT6 appears to regulate the expression of forkhead box M1 (FOXM1), a critical transcription factor for cell cycle progression and senescence. Overexpression of FOXM1 ameliorates SIRT6 deficiency-induced endothelial cell senescence. In this work, we demonstrate the role of SIRT6 as an anti-aging factor in the vasculature. These data may provide the basis for future novel therapeutic approaches against age-related vascular disorders.

Sirtuin 6 Protects Against Oxidative Stress and Vascular Dysfunction in Mice

“…Furthermore, we only studied haploinsufficient mice herein, as knockout of SIRT6 in our experience results in dramatic blunting of animal growth and high mortality, and removal of aorta from such mice was not successful without significant damaging of the vessel. Nevertheless, prior work suggests that induction of premature senescence is a consequence of SIRT6 inactivation in vitro ( Lee et al, 2020 ), which can subsequently increase Nox2 activity ( Huang et al, 2017 ) (a phenomenon demonstrated in kidney). Ultimately, we feel these are exciting new directions for investigation in the field moving forward.…”

Induction of senescence upon loss of the Ash2l core subunit of H3K4 methyltransferase complexes

“…Also, in several cellular systems, the exogenous expression of FoxM1 was sufficient to interfere with induction of senescence (e.g. 57, 58, 59, 60, 61 ). High mobility group proteins, including Hmgb2, possess functions in the control of chromatin and its downregulation is an early marker for senescence and aging 35, 62, 63 .…”

Mammalian Sirtuins and Their Relevance in Vascular Calcification

“…Jin et al studied the role of SIRT6 in minute cholesterol crystals and concluded that SIRT6 could inhibit cholesterol crystal-induced endothelial dysfunction by activating Nrf2 ( Jin et al, 2020 ). EC dysfunction and senescence can be promoted by SIRT6 deficiency, and the mechanism involves the downregulation of forkhead box M1 expression ( Lee et al, 2020b ). In addition to VSMCs and ECs, the normal expression of SIRT6 in bone marrow-derived cells has functional implications.…”