Published online before print September 7, 2006, doi: 10.1161/01.RES.0000244015.10655.3f
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Submitted on October 25, 2005
Revised on July 19, 2006
Accepted on August 24, 2006
RhoA Mediates Angiotensin II-Induced Phospho-Ser536 Nuclear Factor 
B/RelA Subunit Exchange on the Interleukin-6 Promoter in VSMCs
Ruwen Cui ;
From the Department of Medicine (R.C., B.T., A.R., R.G.T., A.R.B.), Department of Biochemistry and Molecular Biology (B.T.), Stark Diabetes Center (R.G.T.), and Center for Molecular Medicine (A.R.B.), University of Texas Medical Branch, Galveston.
* To whom correspondence should be addressed. E-mail: arbrasie{at}utmb.edu.
The vasoconstrictor angiotensin II (A-II) accelerates atherosclerosis by inducing vascular gene expression programs, producing monocyte recruitment, and vascular remodeling. In vascular smooth muscle cells (VSMCs), A-II signaling activates interleukin (IL)-6 expression, a cytokine producing acute-phase inflammation, mediated by the transcription factor nuclear factor 
B (NF-B). The classical NF-B activation pathway involves cytoplasmic-to-nuclear translocation of the potent RelA transactivating subunit; however, because nuclear RelA is present in VSMCs, the mechanism by which NF-B activity is controlled is incompletely understood. In this study, we focus on early activation steps controlling RelA activation. Although A-II only weakly induces 
1.5-fold RelA nuclear translocation, RelA is nevertheless required because short interfering RNA-mediated RelA knockdown inhibits inducible IL-6 expression. We find instead that A-II stimulation rapidly induces RelA phosphorylation at serine residue 536, a critical regulatory site in its transactivating domain. Chromatin immunoprecipitation assays indicate no significant changes in total RelA binding to the native IL-6 promoter, but an apparent increase in fractional binding of phospho-Ser536 RelA. Inactivation of RhoA by treatment with Clostridium botulinum exoenzyme C3 exotoxin or expression of dominant negative RhoA blocks A-II-inducible RelA Ser536 phosphorylation and IL-6 expression. Finally, enhanced phospho-Ser536 RelA formation in the aortae of rats chronically infused with A-II was observed. Together, these data indicate a novel mechanism for A-II-induced NF-B activation in VSMCs, mediated by RhoA-induced phospho-Ser536 RelA formation, IL-6 expression, and vascular inflammation.
Key words: RhoA • nuclear factor
B •
vascular inflammation •
atherosclerosis
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