Abstract
SIRT6 is an important member of sirtuin family that represses inflammation, aging and DNA damage, three of which are causing factors for endothelial dysfunction. SIRT6 expression is decreased in atherosclerotic lesions from ApoE−/− mice and human patients. However, the role of SIRT6 in regulating vascular endothelial function and atherosclerosis is not well understood. Here we show that SIRT6 protects against endothelial dysfunction and atherosclerosis. Global and endothelium-specific SIRT6 knockout mice exhibited impaired endothelium-dependent vasorelaxation. Moreover, SIRT6+/− haploinsufficient mice fed a high-fat diet (HFD) also displayed impaired endothelium-dependent vasorelaxation. Importantly, SIRT6+/−;ApoE−/− mice after HFD feeding exhibited exacerbated atherosclerotic lesion development, concurrent with increased expression of the proinflammatory cytokine VCAM-1. Loss- and gain-of-SIRT6 function studies in cultured human endothelial cells (ECs) showed that SIRT6 attenuated monocyte adhesion to ECs. RNA-sequencing profiling revealed that SIRT6 overexpression decreased the expression of multiple atherosclerosis-related genes, including proatherogenic gene TNFSF4 (tumor necrosis factor superfamily member 4). Chromatin immunoprecipitation assays showed that SIRT6 decreased TNFSF4 gene expression by binding to and deacetylating H3K9 at TNFSF4 gene promoter. Collectively, these findings demonstrate that SIRT6 play a pivotal role in maintaining endothelial function and increased SIRT6 activity could be a new therapeutic strategy to combat atherosclerotic disease.
Highlights
Atherosclerosis is a chronic inflammatory disease that develops over decades leading to the clinical events of cardiovascular disease such as heart attacks and strokes
SIRT6 expression is decreased in endothelial cells (ECs) under chronic stimulation with lipopolysaccharide (LPS) [18], hydrogen peroxide (H2O2) [21] and high glucose [2325], three of which are risk factors associated with endothelial dysfunction and atherogenesis
Our results indicate that SIRT6 binds to promoter region of TNFSF4 under basal conditions (Figure 8A), which was increased upon infection with SIRT6 adenovirus
Summary
Atherosclerosis is a chronic inflammatory disease that develops over decades leading to the clinical events of cardiovascular disease such as heart attacks and strokes. Atherosclerosis commences with the trapping of lipoproteins in the vessel wall by modified proteoglycans [1, 2] followed by disruption and dysfunction of the vascular endothelium and a complex inflammatory reaction involving multiple immune cells some of which promote the development of the atherosclerotic plaques [3,4,5]. Besides current cholesterol lowering therapy for the treatment of atherosclerosis, preferable therapies that address the disease process in the vessel wall are needed. One such potential strategy is to correct endothelial dysfunction, which is evidenced by impaired endothelium-dependent vasorelaxation, upregulation of adhesion molecules and increased leukocyte adhesion and invasion, eventually resulting in www.impactaging.com. Further understanding of the atheroprotective role of SIRT6 would facilitate the translational exploitation of SIRT6 based therapeutic approaches in treating CAD
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