SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 37; pp. 14855 - 14860
• Main Authors: Mattagajasingh, Ilwola, Kim, Cuk-Seong, Naqvi, Asma, Yamamori, Tohru, Hoffman, Timothy A, Jung, Saet-Byel, DeRicco, Jeremy, Kasuno, Kenji, Irani, Kaikobad
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.09.2007; National Acad Sciences
• Subjects: Acetylation; Animals; Antibodies; Aorta, Thoracic - cytology; arteries; biochemical pathways; Biological Sciences; Blood pressure; Catalytic activity; Cells, Cultured; Cercopithecus aethiops; COS Cells; DNA, Complementary; Endothelial cells; endothelial nitric oxide synthase; Endothelium; Endothelium, Vascular - cytology; Endothelium, Vascular - physiology; energy intake; Enzyme Activation - drug effects; Human umbilical vein endothelial cells; Humans; longevity; low calorie diet; Metabolism; Mice; Nitrates - analysis; Nitric oxide; Nitric Oxide Synthase Type III - analysis; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Nitrites - analysis; Obesity; overweight; Oxides; Proteins; Rats; Recombinant Proteins - metabolism; RNA Interference; Sirtuin 1; Sirtuins - metabolism; Sirtuins - pharmacology; Sodium; Transfection; Umbilical Veins - cytology; Vasodilation; Veins & arteries
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0704329104

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.