title: SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase.
abstract: Reduced caloric intake decreases arterial blood pressure in healthy individuals and improves endothelium-dependent vasodilation in obese and overweight individuals. The SIRT1 protein deacetylase mediates many of the effects of calorie restriction (CR) on organismal lifespan and metabolic pathways. However, the role of SIRT1 in regulating endothelium-dependent vasomotor tone is not known. Here we show that SIRT1 promotes endothelium-dependent vasodilation by targeting endothelial nitric oxide synthase (eNOS) for deacetylation. SIRT1 and eNOS colocalize and coprecipitate in endothelial cells, and SIRT1 deacetylates eNOS, stimulating eNOS activity and increasing endothelial nitric oxide (NO). SIRT1-induced increase in endothelial NO is mediated through lysines 496 and 506 in the calmodulin-binding domain of eNOS. Inhibition of SIRT1 in the endothelium of arteries inhibits endothelium-dependent vasodilation and decreases bioavailable NO. Finally, CR of mice leads to deacetylation of eNOS. Our results demonstrate that SIRT1 plays a fundamental role in regulating endothelial NO and endothelium-dependent vascular tone by deacetylating eNOS. Furthermore, our results provide a possible molecular mechanism connecting the effects of CR on the endothelium and vascular tone to SIRT1-mediated deacetylation of eNOS.
authors.affiliation: Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
authors.forename: Ilwola
authors.initials: I
authors.lastname: Mattagajasingh
authors.forename: Cuk-Seong
authors.initials: CS
authors.lastname: Kim
authors.forename: Asma
authors.initials: A
authors.lastname: Naqvi
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamori
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hoffman
authors.forename: Saet-Byel
authors.initials: SB
authors.lastname: Jung
authors.forename: Jeremy
authors.initials: J
authors.lastname: DeRicco
authors.forename: Kenji
authors.initials: K
authors.lastname: Kasuno
authors.forename: Kaikobad
authors.initials: K
authors.lastname: Irani
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018076:DNA, Complementary; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009566:Nitrates / Q000032:analysis; D052250:Nitric Oxide Synthase Type III / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D009573:Nitrites / Q000032:analysis; D034622:RNA Interference; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology; D014664:Vasodilation