Vascular Smooth Muscle Sirtuin-1 Protects Against Diet-Induced Aortic Stiffness

Abstract

Arterial stiffness, a major cardiovascular risk factor, develops within two months in mice fed a high fat, high sucrose diet (HFHS), serving as a model of human metabolic syndrome, and is associated with activation of pro-inflammatory and oxidant pathways in vascular smooth muscle (VSM) cells. Sirtuin-1 (SirT1) is an NAD ⁺-dependent deacetylase regulated by the cellular metabolic status. Our goal was to study the effects of VSM SirT1 on arterial stiffness in the context of diet-induced metabolic syndrome.

Overnight fasting acutely decreased arterial stiffness, measured in vivo by pulse wave velocity (PWV), in mice fed HFHS for 2 or 8 months, but not in mice lacking SirT1 in VSM (SMKO). Similarly, VSM specific (SMTG) genetic SirT1 over-expression prevented PWV increases induced by HFHS feeding, over 8 months. Administration of resveratrol or S17834, two polyphenolic compounds known to activate SirT1, prevented HFHS-induced arterial stiffness and were mimicked by global SirT1 over-expression (SirBACO), without evident metabolic improvements. Additionally, HFHS-induced PWV increases were reversed by one-week treatment with a specific, small molecule SirT1 activator (SRT1720). These beneficial effects of pharmacological or genetic SirT1 activation, against HFHS-induced arterial stiffness, were associated with a decrease in NFκB activation and VCAM-1 and p47phox protein expressions, in aorta and VSM cells.

In conclusion, VSM SirT1 activation decreases arterial stiffness in the setting of obesity by stimulating anti-inflammatory and anti-oxidant pathways in the aorta. SirT1 activators may represent a novel therapeutic approach to prevent arterial stiffness and associated cardiovascular complications in overweight/obese individuals with metabolic syndrome.