Journal article
SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase
Proceedings of the National Academy of Sciences - PNAS, Vol.104(37), pp.14855-14860
09/11/2007
DOI: 10.1073/pnas.0704329104
PMCID: PMC1976244
PMID: 17785417
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.
Details
- Title: Subtitle
- SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase
- Creators
- Ilwola Mattagajasingh - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213Cuk-Seong Kim - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213Asma Naqvi - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213Tohru Yamamori - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213Timothy A Hoffman - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213Saet-Byel Jung - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213Jeremy DeRicco - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213Kenji Kasuno - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213Kaikobad Irani - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.104(37), pp.14855-14860
- DOI
- 10.1073/pnas.0704329104
- PMID
- 17785417
- PMCID
- PMC1976244
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 09/11/2007
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984047713902771
Metrics
15 Record Views