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Thesis Format

Integrated Article


Master of Science


Medical Biophysics


Dr. J. Geoffrey Pickering


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.

Summary for Lay Audience

Cardiovascular diseases are the leading cause of death worldwide. Many of these diseases arise when a critical component of blood vessels called the vascular smooth muscle cell (VSMC) does not function properly. We and others have found that the absence of a protein within the body called sirtuin 6 (Sirt6) may lead to catastrophic dysfunction of blood vessels. Therefore, the purpose of this thesis was to examine how this process may work in mouse VSMCs.

I created a model of VSMCs that lack the gene for Sirt6. I then investigated the genes that are increased or decreased in the absence of Sirt6. In this study, I discovered a pathway that stimulates aggressive inflammation of blood vessels.

This knowledge could help in developing diagnostic techniques or therapies aimed at preventing the development of inflammatory vascular diseases.

Available for download on Saturday, June 29, 2024