Histone Deacetylase 3 Antagonizes Aspirin-Stimulated Endothelial Nitric Oxide Production by Reversing Aspirin-Induced Lysine Acetylation of Endothelial Nitric Oxide Synthase

Saet-Byel JUNG; Cuk-Seong KIM; Kaikobad IRANI; Asma NAQVI; Tohru YAMAMORI; Ilwola MATTAGAJASINGH; Timothy A HOFFMAN; Marsha P COLE; Ajay KUMAR; Jeremy S DERICCO; Byeong-Hwa JEON

doi:10.1161/CIRCRESAHA.110.222968

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Histone Deacetylase 3 Antagonizes Aspirin-Stimulated Endothelial Nitric Oxide Production by Reversing Aspirin-Induced Lysine Acetylation of Endothelial Nitric Oxide Synthase

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Histone Deacetylase 3 Antagonizes Aspirin-Stimulated Endothelial Nitric Oxide Production by Reversing Aspirin-Induced Lysine Acetylation of Endothelial Nitric Oxide Synthase

Saet-Byel JUNG, Cuk-Seong KIM, Kaikobad IRANI, Asma NAQVI, Tohru YAMAMORI, Ilwola MATTAGAJASINGH, Timothy A HOFFMAN, Marsha P COLE, Ajay KUMAR, Jeremy S DERICCO, …

Circulation research, Vol.107(7), pp.877-887

2010

DOI: 10.1161/CIRCRESAHA.110.222968

PMCID: PMC3025612

PMID: 20705923

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Abstract

Rationale: Low-dose acetylsalicylic acid (aspirin) is widely used in the treatment and prevention of vascular atherothrombosis. Cardiovascular doses of aspirin also reduce systemic blood pressure and improve endothelium-dependent vasorelaxation in patients with atherosclerosis or risk factors for atherosclerosis. Aspirin can acetylate proteins, other than its pharmacological target cyclooxygenase, at lysine residues. The role of lysine acetylation in mediating the effects of low-dose aspirin on the endothelium is not known. Objective: To determine the role of lysine acetylation of endothelial nitric oxide synthase (eNOS) in the regulation of endothelial NO production by low-dose aspirin and to examine whether the lysine deacetylase histone deacetylase (HDAC)3 antagonizes the effect of low-dose aspirin on endothelial NO production by reversing acetylation of functionally critical eNOS lysine residues. Methods and results: Low concentrations of aspirin induce lysine acetylation of eNOS, stimulating eNOS enzymatic activity and endothelial NO production in a cyclooxygenase-1-independent fashion. Low-dose aspirin in vivo also increases bioavailable vascular NO in an eNOS-dependent and cyclooxygenase-1-independent manner. Low-dose aspirin promotes the binding of eNOS to calmodulin. Lysine 609 in the calmodulin autoinhibitory domain of bovine eNOS mediates aspirin-stimulated binding of eNOS to calmodulin and eNOS-derived NO production. HDAC3 inhibits aspirin-stimulated (1) lysine acetylation of eNOS, (2) eNOS enzymatic activity, (3) eNOS-derived NO, and (4) binding of eNOS to calmodulin. Conversely, downregulation of HDAC3 promotes lysine acetylation of eNOS and endothelial NO generation. Conclusions: Lysine acetylation of eNOS is a posttranslational protein modification supporting low-dose aspirin-induced vasoprotection. HDAC3, by deacetylating aspirin-acetylated eNOS, antagonizes aspirin-stimulated endothelial production of NO.

Fundamental and applied biological sciences. Psychology

Biological and medical sciences

Vertebrates: cardiovascular system

Details

Title: Subtitle: Histone Deacetylase 3 Antagonizes Aspirin-Stimulated Endothelial Nitric Oxide Production by Reversing Aspirin-Induced Lysine Acetylation of Endothelial Nitric Oxide Synthase
Creators: Saet-Byel JUNG - Cardiovascular Institute, University of Pittsburgh Medical Center, Pa, United States
Cuk-Seong KIM - Cardiovascular Institute, University of Pittsburgh Medical Center, Pa, United States
Kaikobad IRANI - Cardiovascular Institute, University of Pittsburgh Medical Center, Pa, United States
Asma NAQVI - Cardiovascular Institute, University of Pittsburgh Medical Center, Pa, United States
Tohru YAMAMORI - Cardiovascular Institute, University of Pittsburgh Medical Center, Pa, United States
Ilwola MATTAGAJASINGH - Cardiovascular Institute, University of Pittsburgh Medical Center, Pa, United States
Timothy A HOFFMAN - Cardiovascular Institute, University of Pittsburgh Medical Center, Pa, United States
Marsha P COLE - Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center, Pa, United States
Ajay KUMAR - Cardiovascular Institute, University of Pittsburgh Medical Center, Pa, United States
Jeremy S DERICCO - Cardiovascular Institute, University of Pittsburgh Medical Center, Pa, United States
Byeong-Hwa JEON - Department of Physiology, Chungnam National University, Daejeon, Korea, Republic of
Resource Type: Journal article
Publication Details: Circulation research, Vol.107(7), pp.877-887
DOI: 10.1161/CIRCRESAHA.110.222968
PMID: 20705923
PMCID: PMC3025612
NLM abbreviation: Circ Res
ISSN: 0009-7330
eISSN: 1524-4571
Publisher: Lippincott Williams & Wilkins; Hagerstown, MD
Language: English
Date published: 2010
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984047880102771

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