Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6155850 | Translational Research | 2016 | 38 Pages |
Abstract
Sirtuin 6 (SIRT6) is a chromatin-associated deacetylase that plays a leading role in genomic stability and aging. However, the precise role of SIRT6 in atherosclerosis, an aging-associated cardiovascular disease, remains elusive. This study aims at defining the role of SIRT6 in atherosclerotic lesion development. SIRT6 messenger RNA and protein expression are markedly decreased in atherosclerotic aortas of apolipoprotein E-deficient (ApoEâ/â) mice fed a high-cholesterol diet. SIRT6 was knocked down in ApoEâ/â mice using small hairpin RNAs (shRNAs) lentivirus injection. SIRT6-shRNA-treated ApoEâ/â mice showed impaired endothelium-dependent vasodilation, increased plaque size (in aortic sinus, aortic root and en face aorta), and augmented plaque vulnerability (evidenced by increased necrotic core areas and macrophage accumulation and reduced collagen content). At the cellular level, SIRT6 depletion by RNA interference in human umbilical vein endothelial cells significantly increased monocyte adhesion to endothelial cells by inducing the expression of intracellular adhesion molecule-1. Consistently, intracellular adhesion molecule-1 expression was significantly upregulated in aortic endothelium of SIRT6-shRNA-treated ApoEâ/â mice compared with controls. In sum, the aforementioned findings suggest that SIRT6 is a primary negative regulation factor in endothelial dysfunction and atherosclerosis development. As a result, SIRT6 is a promising therapeutic target for treating atherosclerosis and its cardiovascular complications.
Keywords
mRNAmouse aortic endothelial cellsMAECssirtuin 6SIRT6OROVCAM-1MCP-1HUVECHCDICAM-1NF-κBHDLshRNAGAPDHApoE−/−high-density lipoproteinmessenger RNASmall interfering RNAsmall hairpin RNAsiRNAOil red OHigh-cholesterol dietHuman umbilical vein endothelial cellsnuclear factor-κBLow-density lipoproteinLDLintracellular adhesion molecule-1vascular cellular adhesion molecule-1monocyte chemotactic protein 1glyceraldehyde-3-phosphate dehydrogenase
Related Topics
Health Sciences
Medicine and Dentistry
Medicine and Dentistry (General)
Authors
Zhiping Liu, Jiaojiao Wang, Xiaoyang Huang, Zhuoming Li, Peiqing Liu,