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Research Paper|Volume 8, Issue 5|pp 1064—1078

SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

Suowen Xu1, Meimei Yin1, Marina Koroleva1, Michael A. A. Mastrangelo1, Wenbo Zhang2, Peter Bai3,4,5, Peter J. J. Little6, Zheng Gen Gen Jin1
  • 1Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14620, USA
  • 2Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA
  • 3Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
  • 4MTA-DE Lendület Laboratory of Cellular Metabolism Research Group, Debrecen, Hungary
  • 5Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
  • 6School of Pharmacy, The University of Queensland, Pharmacy Australia Centre of Excellence (PACE), Woolloongabba QLD 4102, Australia
Received: April 18, 2016Accepted: May 18, 2016Published: May 30, 2016
https://doi.org/10.18632/aging.100975

Copyright: © 2016 Xu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.