Deletion of sirtuin 6 accelerates endothelial dysfunction and atherosclerosis in apolipoprotein E-deficient mice

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• 作者：Zhiping Liu^a ; ^b ; ^c ; Jiaojiao Wang^a ; ^b ; ^c ; Xiaoyang Huang^a ; ^b ; ^c ; Zhuoming Li^a ; ^b ; ^c ; ^{lizhm5@mail.sysu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Peiqing Liu^a ; ^b ; ^c ; ^{liupq@mail.sysu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ApoE&minus ; /&minus ; apolipoprotein E&ndash ; deficient ; GAPDH ; glyceraldehyde-3-phosphate dehydrogenase ; HCD ; high-cholesterol diet ; HDL ; high-density lipoprotein ; HUVEC ; human umbilical vein endothelial cells ; ICAM-1 ; intracellular adhesion molecule-1 ; LDL ; low-density lipoprotein ; MAECs ; mouse aortic endothelial cells ; MCP-1 ; monocyte chemotactic protein 1 ; mRNA ; messenger RNA ; NF-κB ; nuclear factor-κB ; ORO ; Oil Red O ; shRNA ; small hairpin RNA ; siRNA ; small interfering RNA ; SIRT6 ; sirtuin 6 ; VC
• 刊名：Translational Research
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：172
• 期：Complete
• 页码：18-29.e2
• 全文大小：3464 K

文摘

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 (ApoE^−/−) mice fed a high-cholesterol diet. SIRT6 was knocked down in ApoE^−/− mice using small hairpin RNAs (shRNAs) lentivirus injection. SIRT6-shRNA–treated ApoE^−/− 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 ApoE^−/− 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.