SIRT6 Mediated Vascular Smooth Muscle Cells Senescence Participates in the Pathogenesis of Abdominal Aortic Aneurysm

Abstract

Objective Sirtuin 6 (SIRT6) is a nuclear deacetylase regulating lifespan. Previous articles had reported a causal link between cell senescence and aneurysm. In this study, we carried out clinical sample study, in vivo study and in vitro study to determine the effect of SIRT6 and SIRT6 mediated vascular smooth muscle senescence on the development of AAA (abdominal aortic aneurysm) Methods Aortic specimens were collected from AAA patients and organ donors. AAA was inducted in ApoE−/− mice by Angiotensin II infusion. In vivo overexpression of SIRT6 was achieved by transgenic method. Human aortic smooth muscle cells (HASMC) were used in the in vitro study. In vitro knockdown and overexpression of SIRT6 was achieved by lentivirus transfection. Results AAA specimen showed an increased P16, P21 level and a decreased SIRT6 level compared with control aorta. Time cause study of Ang II infusion model showed similar P16, P21 and SIRT6 change at the early phase of AAA induction. The in vivo overexpression of SIRT6 significantly prevented AAA formation in Ang II infusion model. The expression of senescent biomarker, P16 and P21 were significantly reduced after SIRT6 overexpression. SIRT6 overexpression also attenuated chronic inflammation and neo-angiogenesis in Ang II infusion model. Ang II could induce premature senescence in HASMC. The overexpression of SIRT6 could attenuated premature senescence, inflammatory response and neo-angiogenesis in HASMC under Ang II stimulation. Conclusion SIRT6 overexpression could limit AAA formation via attenuate vascular smooth muscle senescence, chronic inflammation and neovascularity.