title: 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 (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.
authors.affiliation: From the Vascular Biology Section, School of Medicine, Boston University Medical Campus, MA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Fry
authors.affiliation: From the Vascular Biology Section, School of Medicine, Boston University Medical Campus, MA.
authors.forename: Leona
authors.initials: L
authors.lastname: Al Sayah
authors.affiliation: From the Vascular Biology Section, School of Medicine, Boston University Medical Campus, MA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weisbrod
authors.affiliation: From the Vascular Biology Section, School of Medicine, Boston University Medical Campus, MA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Roy
authors.affiliation: From the Vascular Biology Section, School of Medicine, Boston University Medical Campus, MA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Weng
authors.affiliation: From the Vascular Biology Section, School of Medicine, Boston University Medical Campus, MA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cohen
authors.affiliation: From the Vascular Biology Section, School of Medicine, Boston University Medical Campus, MA.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Bachschmid
authors.affiliation: From the Vascular Biology Section, School of Medicine, Boston University Medical Campus, MA. setaf@bu.edu.
authors.forename: Francesca
authors.initials: F
authors.lastname: Seta
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002318:Cardiovascular Diseases / Q000517:prevention & control; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test; D008297:Male; D024821:Metabolic Syndrome / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009765:Obesity / Q000503:physiopathology*; D063177:Pulse Wave Analysis; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D059289:Vascular Stiffness / Q000187:drug effects*
chemical_list: D013267:Stilbenes; D019010:Vascular Cell Adhesion Molecule-1; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: aorta; arterial stiffness; cardiovascular disease metabolic syndrome obesity sirtuin-1 vascular smooth muscle