ABSTRACT
Arterial stiffness, a major cardiovascular risk factor, develops within 2 months in mice fed a high-fat, high-sucrose (HFHS) diet, serving as a model of human metabolic syndrome, and it is associated with activation of proinflammatory 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, in mice fed HFHS for 2 or 8 months, but not in mice lacking SirT1 in VSM (SMKO). Similarly, VSM-specific genetic SirT1 overexpression (SMTG) prevented pulse wave velocity increases induced by HFHS feeding, during 8 months. Administration of resveratrol or S17834, 2 polyphenolic compounds known to activate SirT1, prevented HFHS-induced arterial stiffness and were mimicked by global SirT1 overexpression (SirT1 bacterial artificial chromosome overexpressor), without evident metabolic improvements. In addition, HFHS-induced pulse wave velocity increases were reversed by 1-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 nuclear factor kappa light chain enhancer of activated B cells (NFκB) activation and vascular cell adhesion molecule (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 antioxidant 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.
Subject(s)
Diet, High-Fat/adverse effects , Obesity/physiopathology , Sirtuin 1/pharmacology , Vascular Cell Adhesion Molecule-1/metabolism , Vascular Stiffness/drug effects , Animals , Blotting, Western , Cardiovascular Diseases/prevention & control , Disease Models, Animal , Glucose Tolerance Test , Male , Metabolic Syndrome/prevention & control , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Pulse Wave Analysis , Random Allocation , Real-Time Polymerase Chain Reaction , Resveratrol , Stilbenes/pharmacologyABSTRACT
Stiffening of conduit arteries is a risk factor for cardiovascular morbidity. Aortic wall stiffening increases pulsatile hemodynamic forces that are detrimental to the microcirculation in highly perfused organs, such as the heart, brain, and kidney. Arterial stiffness is associated with hypertension but presumed to be due to an adaptive response to increased hemodynamic load. In contrast, a recent clinical study found that stiffness precedes and may contribute to the development of hypertension although the mechanisms underlying hypertension are unknown. Here, we report that in a diet-induced model of obesity, arterial stiffness, measured in vivo, develops within 1 month of the initiation of the diet and precedes the development of hypertension by 5 months. Diet-induced obese mice recapitulate the metabolic syndrome and are characterized by inflammation in visceral fat and aorta. Normalization of the metabolic state by weight loss resulted in return of arterial stiffness and blood pressure to normal. Our findings support the hypothesis that arterial stiffness is a cause rather than a consequence of hypertension.
