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(Circulation Research. 2006;99:723.)
© 2006 American Heart Association, Inc.

Molecular Medicine

RhoA Mediates Angiotensin II–Induced Phospho-Ser536 Nuclear Factor B/RelA Subunit Exchange on the Interleukin-6 Promoter in VSMCs

Ruwen Cui, Brian Tieu, Adrian Recinos, Ronald G. Tilton, Allan R. Brasier

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 Sealy Center for Molecular Medicine (A.R.B.), University of Texas Medical Branch, Galveston.

Correspondence to Allan R. Brasier, Division of Endocrinology, MRB 8.128, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1060. Email arbrasie{at}utmb.edu

The vasoconstrictor angiotensin II (Ang II) accelerates atherosclerosis by inducing vascular gene expression programs, producing monocyte recruitment, and vascular remodeling. In vascular smooth muscle cells (VSMCs), Ang 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 Ang 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 Ang 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 Ang II–inducible RelA Ser536 phosphorylation and IL-6 expression. Finally, enhanced phospho-Ser536 RelA formation in the aortae of rats chronically infused with Ang II was observed. Together, these data indicate a novel mechanism for Ang 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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