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SIRT6 protects against endothelial dysfunction and atherosclerosis in mice
- Source :
- Scopus-Elsevier, Aging (Albany NY), ResearcherID
- Publication Year :
- 2016
- Publisher :
- Impact Journals, LLC, 2016.
-
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.
- Subjects :
- 0301 basic medicine
SIRT6
Aging
medicine.medical_specialty
Vascular Cell Adhesion Molecule-1
OX40 Ligand
Inflammation
Haploinsufficiency
endothelial dysfunction
Proinflammatory cytokine
Mice
03 medical and health sciences
Apolipoproteins E
0302 clinical medicine
Internal medicine
Cell Adhesion
medicine
Animals
Humans
Sirtuins
vascular inflammation
Elméleti orvostudományok
Endothelial dysfunction
Cells, Cultured
Mice, Knockout
Membrane Glycoproteins
biology
Endothelial Cells
Orvostudományok
Cell Biology
Atherosclerosis
medicine.disease
Vasodilation
Vascular endothelial growth factor B
030104 developmental biology
Endocrinology
Tumor Necrosis Factors
Sirtuin
Knockout mouse
Immunology
biology.protein
Tumor necrosis factor alpha
Endothelium, Vascular
RNA-seq
medicine.symptom
030217 neurology & neurosurgery
Research Paper
Subjects
Details
- ISSN :
- 19454589
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Aging
- Accession number :
- edsair.doi.dedup.....cb965280a751b52557841f9e9c619402