Abstract
Cellular senescence of endothelial cells causes vascular dysfunction, promotes atherosclerosis, and contributes to 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.
Highlights
Vascular aging is accompanied by dysfunctional vascular phenotypes including endothelial dysfunction and arterial stiffening that play critical causal roles in the majority of cardiovascular diseases [1,2,3]
Western blot analysis showed that sirtuin 1 (SIRT1) and Sirtuin 6 (SIRT6) expression was significantly reduced on days 3, 5, and 10 following H2O2 treatment (Figure 1C)
In keeping with the pattern of SIRT expression in the oxidative stress-induced senescence of endothelial cells, old endothelial cells showed a clear decrease in SIRT1 and SIRT6 expression and an increase in SIRT3 expression (Figure 1F)
Summary
Vascular aging is accompanied by dysfunctional vascular phenotypes including endothelial dysfunction and arterial stiffening that play critical causal roles in the majority of cardiovascular diseases [1,2,3]. Senescent endothelial cells show impaired homeostatic functions including nitric oxide production, vascular inflammation, cytoskeleton integrity, angiogenesis, proliferation, and cell migration [4, 5]. Among the seven known sirtuins, sirtuin 1 (SIRT1) is the most extensively analyzed sirtuin in endothelial cells and is known to be an important regulator of vascular endothelial aging by preventing DNA damage, cell cycle arrest, and oxidative stress [10]. Loss of SIRT6 is known to associate with vascular endothelial dysfunction, senescence, and inflammation [15, 16], whereas induction of SIRT6 expression by exogenous vector-driven SIRT6, antioxidant, and antiinflammatory signals prevents or ameliorates endothelial dysfunction, senescence, and inflammation [16, 17]. We investigated the role of SIRT6 in relation to the senescent phenotypes of endothelial cells and the pathway responsible for the SIRT6-associated senescence in endothelial cells
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