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J. Biol. Chem., Vol. 281, Issue 19, 13275-13284, May 12, 2006
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The Proinflammatory Actions of Angiotensin II Are Dependent on p65 Phosphorylation by the I
B Kinase Complex*
From the Faculty of Pharmacy, University of Montreal, Montreal, Quebec H3C 3J7, Canada
The vasoactive hormone angiotensin II (Ang II) probably triggers inflammatory cardiovascular diseases by activating transcription factors such as NF-
B. We describe here a novel mode of NF-B activation in cultured vascular smooth muscle cells exposed to Ang II. Ang II treatment resulted in an increase in the phosphotransferase activity of the IKK complex, which was mediated through the AT1 receptor subtype. The typical phosphorylation and proteasome-dependent degradation of the NF-B inhibitor IB
were not observed. Rather, Ang II treatment of vascular smooth muscle cells led to the phosphorylation of p65 on serine 536, a signal detected in both the cytoplasm and the nuclear compartments. The use of pharmacological inhibitors that inhibit the activation of MEK by Ang II revealed that phosphorylation of p65 on serine 536 did not require the MEK-ERK-RSK signaling pathway. On the other hand, specifically targeting the IKK
subunit of the IKK complex by overexpression of a dominant negative version of IKK (IKK K44A) or silencing RNA technology demonstrated that the IKK subunit of the IKK complex was responsible for the detected phosphoserine 536 signal in Ang II-treated cells. Characterization of the signaling pathway leading to activation of the IKK complex by Ang II revealed that neither epidermal growth factor receptor transactivation nor the phosphatidylinositol 3-kinase-AKT signaling cascade were involved. Collectively, our data demonstrate that the proinflammatory activity of Ang II is independent of the classical pathway leading to IB phosphorylation and degradation but clearly depends on the recruitment of an IKK complex signaling cascade leading to phosphorylation of p65 on serine 536.
Received for publication, November 30, 2005 , and in revised form, February 22, 2006.
* This work was supported by a research grant from the Canadian Institutes of Health Research (to M. S.). 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.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.
1 These authors contributed equally to this work.
2 Recipients of a studentship from the Fonds de la Recherche en Santé du Québec (FRSQ).
3 Holds a studentship from Canada's Research-based Pharmaceutical Companies Health Research Foundation/Canadian Institutes of Health Research.
4 Canadian Institutes of Health Research scholar.
5 To whom correspondence should be addressed: P. O. Box 6128, Downtown station, Montreal, Quebec H3C 3J7, Canada. Tel.: 514-343-7966; Fax: 514-343-7073; E-mail: marc.servant{at}umontreal.ca.
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