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

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 (NF?B) 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.

SUBMITTER: Fry JL

PROVIDER: S-EPMC4982825 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Fry Jessica L JL Al Sayah Leona L Weisbrod Robert M RM Van Roy Isabelle I Weng Xiang X Cohen Richard A RA Bachschmid Markus M MM Seta Francesca F

Hypertension (Dallas, Tex. : 1979) 20160718 3

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 metaboli ...[more]

PMID: 27432859

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Project description:AIMS:Peroxisome proliferator-activated receptor ? (PPAR?) agonists reduce blood pressure and vascular injury in hypertensive rodents. Ppar? inactivation in vascular smooth muscle cells (VSMC) enhances vascular injury. Transgenic mice overexpressing endothelin (ET)-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Ppar? gene in VSMC (smPpar?-/-) would exaggerate ET-1-induced vascular injury. METHODS AND RESULTS:eET-1, smPpar?-/- and eET-1/smPpar?-/- mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPpar? inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPpar?-/-. N(omega)-Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPpar?-/-, which could indicate that nitric oxide production was enhanced by ET-1 stimulation of endothelin type B receptors. Mesenteric artery media/lumen was greater only in eET-1/smPpar?-/-. Mesenteric artery reactive oxygen species increased in smPpar? and were further enhanced in eET-1/smPpar?-/-. Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPpar? and increased further in eET-1/smPpar?-/-. Spleen CD11b+ cells were increased in smPpar?-/- and further enhanced in eET-1/smPpar?-/-, whereas Ly-6C(hi) monocytes increased in eET-1 and smPpar?-/- but not in eET-1/smPpar?-/-. Spleen T regulatory lymphocytes increased in smPpar? and decreased in eET-1, and decreased further in eET-1/smPpar?-/-. CONCLUSION:VSMC Ppar? inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPAR? in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPpar?-/- mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.

Dataset Information

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

Publications

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

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