HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 24, 16293-16298, June 13, 2008

This Article Free via Author's Choice: AC AC Full Text Full Text (PDF) AC All Versions of this Article: 283/24/16293    most recent M801803200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chen, W. Articles by Harrison, D. G. Search for Related Content PubMed PubMed Citation Articles by Chen, W. Articles by Harrison, D. G. Social Bookmarking                      What's this?

Activation of p300 Histone Acetyltransferase Activity Is an Early Endothelial Response to Laminar Shear Stress and Is Essential for Stimulation of Endothelial Nitric-oxide Synthase mRNA Transcription^*

Wei Chen, Methode Bacanamwo^¶, and David G. Harrison¹

From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30022, Atlanta Veterans Administration Hospital, Decatur, Georgia 30033, and ^¶Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia 30310

Previous studies have shown that the acute stimulation of endothelial nitric-oxide synthase (eNOS) mRNA transcription by laminar shear stress is dependent on nuclear factor B (NFB) subunits p50 and p65 binding to a shear stress response element (SSRE) in the human eNOS promoter and that mutation of the SSRE abrogates the shear-stimulated increase in eNOS promoter activity. In the present study, we found that although shear markedly increased eNOS mRNA, the increase in nuclear translocation of p50 and p65 caused by shear was only 2-fold, suggesting that shear has additional effects on NFB cofactor activity beyond nuclear translocation. Chromatin immunoprecipitation assays showed that virtually no p50 or p65 was bound to the eNOS promoter at base line but that shear increased the binding of these subunits to the human eNOS SSRE by 10- to 20-fold. Co-immunoprecipitation studies demonstrated during the first 30 min of shear p300 bound to p65. Shear also increased p300 histone acetyltransferase (HAT) activity by 2.5-fold and increased acetylation of p65. The increase in eNOS mRNA caused by shear was completely blocked by pharmacological inhibition of p300/HAT activity with curcumin or by p300 small interfering RNA. Chromatin immunoprecipitation assays also showed that shear stimulated acetylation of histones 3 and 4 at the region of the eNOS promoter SSRE and extended 3' toward the eNOS coding region. This was associated with opening of chromatin at the SSRE. In conclusion, these studies reveal a previously unknown role of p300/HAT activation as a very early response to shear that is essential for increasing eNOS mRNA levels.

Received for publication, March 6, 2008

Author's Choice—Final version full access.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL39006, HL38206, HL59248, and DK51257 and by National Institutes of Health Program Project Grants HL58000 and HL075209. This work was also supported by a Department of Veterans Affairs merit grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Author's Choice

Creative Commons Attribution Non-Commercial License applies to Author Choice Articles

¹ To whom correspondence should be addressed: Cardiology Division, Dept. of Medicine, Rm. 319 WMRB, 1639 Pierce Dr., Atlanta, GA 30022. Tel.: 404-727-3710; Fax: 404-727-8386; E-mail: dharr02{at}emory.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?