SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

Suowen Xu, Meimei Yin, Marina Koroleva, Michael A. Mastrangelo, Wenbo Zhang, Peter Bai, Peter J. Little, Zheng Gen Jin

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1064-1082
Number of pages19
JournalAging
Volume8
Issue number5
StatePublished - 2016

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Endothelium
Atherosclerosis
Tumor Necrosis Factor-alpha
High Fat Diet
Apolipoproteins E
Vasodilation
Endothelial Cells
Genes
RNA Sequence Analysis
Vascular Cell Adhesion Molecule-1
Chromatin Immunoprecipitation
Knockout Mice
DNA Damage
Blood Vessels
Monocytes
Cytokines
Inflammation
Gene Expression
Therapeutics

Keywords

  • Atherosclerosis
  • Endothelial dysfunction
  • RNA-seq
  • SIRT6
  • Vascular inflammation

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Xu, S., Yin, M., Koroleva, M., Mastrangelo, M. A., Zhang, W., Bai, P., ... Jin, Z. G. (2016). SIRT6 protects against endothelial dysfunction and atherosclerosis in mice. Aging, 8(5), 1064-1082.

SIRT6 protects against endothelial dysfunction and atherosclerosis in mice. / Xu, Suowen; Yin, Meimei; Koroleva, Marina; Mastrangelo, Michael A.; Zhang, Wenbo; Bai, Peter; Little, Peter J.; Jin, Zheng Gen.

In: Aging, Vol. 8, No. 5, 2016, p. 1064-1082.

Research output: Contribution to journalArticle

Xu, S, Yin, M, Koroleva, M, Mastrangelo, MA, Zhang, W, Bai, P, Little, PJ & Jin, ZG 2016, 'SIRT6 protects against endothelial dysfunction and atherosclerosis in mice', Aging, vol. 8, no. 5, pp. 1064-1082.
Xu S, Yin M, Koroleva M, Mastrangelo MA, Zhang W, Bai P et al. SIRT6 protects against endothelial dysfunction and atherosclerosis in mice. Aging. 2016;8(5):1064-1082.
Xu, Suowen ; Yin, Meimei ; Koroleva, Marina ; Mastrangelo, Michael A. ; Zhang, Wenbo ; Bai, Peter ; Little, Peter J. ; Jin, Zheng Gen. / SIRT6 protects against endothelial dysfunction and atherosclerosis in mice. In: Aging. 2016 ; Vol. 8, No. 5. pp. 1064-1082.
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