Abstract 5495: Role of SIRT1 in Smooth Muscle Cell Function and Vascular Remodeling

Abstract

Background: The class III histone deacetylase SIRT1 has been identified as a key regulator of ageing and longevity in model organisms such as S. cerevisiae and C. elegans, which regulates cellular functions such as differentiation, senescence and metabolism. However, the role of SIRT1 for Smooth muscle cell (VSMC) function and vascular homeostasis or during vascular remodelling remains unknown. Methods and Results: Here, we show that SIRT1 is highly expressed in intact blood vessels in vivo as well as in cultured VSMC. Stimulation of SIRT1 activity by either treatment with the SIRT1 activator resveratrol or adenoviral overexpression of wild type SIRT1 but not with an inactive SIRT1 mutant attenuated serum-induced VSMC proliferation in a dose dependent manner in vitro. In contrast, treatment of VSMC with the small molecule weight inhibitors of SIRT1, nicotinamide and sirtinol, augmented the proliferative and migratory activity of VSMC. Consistent with these data, MEF cells isolated from SIRT −/− mice showed an augmented proliferative response to serum stimulation but were also more resistant to starving-induced apoptosis compared to WT-MEF cells. Silencing of endogenous SIRT1 using siRNA resulted in an increased proliferation, migration and apoptosis of VSMC. In vivo, following arterial injury of the mouse femoral artery, SIRT1 was downregulated in the developing neointima. Adenoviral-mediated reconstitution of wild type SIRT1 but not of the inactive SIRT1 mutant prevented neointima formation in vivo. Conclusion: Thus, these data identify SIRT1 as a key regulator of vascular proliferative disease processes and indicate that SIRT1 plays an essential role in proliferative migratory and apoptotic processes which regulate vascular homeostasis and remodeling.