Abstract 289: Sirtuin-1 Inhibition by Peroxynitrite Contributes to Nicotine-induced Arterial Stiffness in Mice

Abstract

Cigarette smoking is a key contributor to arterial stiffness, which is a major and independent risk factor for serious cardiovascular events. Sirtuin-1 (SIRT1), a nicotinamide adenine dinucleotide-dependent protein deacetylase, plays an essential role in maintaining cardiovascular homeostasis, and Sirt1 inhibition is linked to smoking-induced arterial damage and aortic stiffness. The mechanism behind key component of cigarette smoking, nicotine-induced SIRT1 inactivation remains unknown; therefore, we aimed to characterize the relationship between nicotine, SIRT1 inhibition, and arterial stiffness. Arterial stiffness and SIRT1 expression and activity in wild-type and Sirt1- overexpressing mice treated with nicotine or vehicle were monitored. Nicotine significantly increased arterial stiffness in wild type, but not Sirt1 -overexpressing mice. Additionally, SIRT1 protein levels and activity were decreased in nicotine-treated wild-type mice, but not in Sirt1- overexpressing mice, and these results were reproducible in human aortic smooth muscle cells. We further determined that SIRT1 inhibition was caused by zinc release from and subsequent inhibition of deacetylation activity of SIRT1, leading to Yes-associated protein activation, and, ultimately, extracellular matrix remodeling associated with arterial stiffness. Zinc release from SIRT1 was mediated by peroxynitrite resulting from nicotine-induced increases in inducible nitric oxide synthase. Taken together, nicotine triggers arterial stiffness via extracellular matrix remodeling mediated by SIRT1 inhibition due to peroxynitrite-induced zinc release from SIRT1.