Characterizing The Transcriptome of Sirt6-Deficient Aortic Smooth Muscle Cells

Ryan J. Wong, The University of Western Ontario

Abstract

Several vascular diseases are marked by dysfunctional vascular smooth muscle cells (VSMCs). Our group has found that the knockout of the NAD⁺-dependent histone deacetylase sirtuin 6 (Sirt6), specifically in VSMCs, increases oxidative stress-induced DNA damage, inflammation, and aortic aneurysms in mice. To study the molecular mechanisms that drive VSMC dysfunction in Sirt6-deficiency, I established a primary culture model of Sirt6 deletion in VSMCs with Cre-lox technology. Through RNA sequencing of Sirt6-deficient VSMCs, we have identified modest but coordinated upregulations in transcripts involved in nucleosome assembly, inflammation, cell death, and autoimmunity. Immunostaining in histological sections of VSMC-specific Sirt6-deficient mice exposed to increased oxidative stress via angiotensin II infusion revealed aberrant localization of proteins normally in the nucleus that could induce inflammation. We propose that aortic Sirt6 has an anti-inflammatory role in the vessel wall.