Role of vascular smooth muscle sirtuin-1 in the development of aortic aneurysm

Abstract

BACKGROUND: Aortic aneurysm (AA) affects 15, 000 individuals in the United States and 221,900 individuals in China die every year due to the dissection and rupture of an AA. Genetic disorders such as Marfan’s syndrome, increase the risk of developing AA. Our work seeks to identify novel molecular mechanisms that could become much needed therapeutic targets to prevent AA. We previously showed that the lysine deacetylase sirtuin-1 (SirT1) is crucial to protect the vascular wall against inflammatory and oxidant insults. We hypothesize that an increased oxidative stress in the vascular wall of patients with Marfan’s syndrome, inhibits SirT1 by oxidative post-translational modifications leading to vascular wall remodeling and AA. METHODS: To test our hypothesis we used fibrillin-1 mutant mice (Fbn1mgR/mgR), a genetic model of Marfan’s syndrome prone to AA, and wild type (WT) controls. Aortic sections or vascular smooth muscle cells (VSMC) homogenates from WT and Fbn1mgR/mgR were prepared and processed for dihydroethidium staining, NAD/NADH measurements and in-gel zymography, respectively. In addition, we generated a mutant sirtuin-1 construct plasmid resistant to oxidative post-translational modifications as a novel tool to determine the role of sirtuin-1 in AA. RESULTS: Our results indicate that there is an increase in oxidative stress and metalloproteinase activity in the thoracic aorta of Fbn1mgR/mgR compared to WT, while NAD/NADH is not significantly increased. In addition, we successfully generated a mutant redox-resistant sirtuin-1 plasmid for future studies. CONCLUSION: Our preliminary data strongly suggest that targeting oxidative stress and/or preventing oxidative post-translational modifications of SirT-1 represent a potential therapeutic avenue to prevent or ameliorate AA in patients as risk, such as those with Marfan’s syndrome