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(Circulation Research. 2005;97:975.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Dual Pathways for Nuclear Factor B Activation by Angiotensin II in Vascular Smooth Muscle

Phosphorylation of p65 by IB Kinase and Ribosomal Kinase

Liping Zhang, Jizhong Cheng, Yewei Ma, Walter Thomas, Jiqiang Zhang, Jie Du

From the Department of Medicine-Nephrology (L.Z., J.C., Y.M., J.Z., J.D.), Baylor College of Medicine, Houston, Tex; and Molecular Endocrinology (W.T.), Baker Heart Research Institute, Melbourne, Victoria, Australia.

Correspondence to Jie Du, BCM 285, One Baylor Plaza, Houston, TX 77030. E-mail jdu{at}bcm.edu

Activation of nuclear factor (NF)-B by angiotensin II (Ang II) plays an essential role in stimulating expression of vascular adhesion molecules, which are essential for vascular inflammation. We report that Ang II activates NF-B by phosphorylating its p65 subunit via a pathway mediated partially by ribosomal S6 kinase (RSK). In investigating other pathway(s) that may be involved, we found that the ability of Ang II to activate NF-B in mouse embryonic fibroblast is suppressed (&70%) either by deletion of IB Kinase (IKK) or by inhibiting or knocking down IKK in vascular smooth muscle cells using a dominant-negative IKK adenovirus or small interference RNA to IKKß. Thus, Ang II also stimulates NF-B via IKK. In vitro, we found that Ang II stimulates IKK to phosphorylate myelin basic protein and the p65 subunit of NF-B. The mechanism by which Ang II activates IKK is to increase phosphorylation of IKKß in its activation loop (Ser181) rather than IB phosphorylation. Inhibiting both the RSK and IKK pathways completely blocks the Ang II–induced p65 phosphorylation and NF-B activation. These 2 pathways are independent: inhibiting IKK does not block Ang II–induced phosphorylation of RSK, whereas inhibiting mitogen-activated protein kinase 1 does not affect phosphorylation of IKK. Finally, we found that Ang II can induce expression of vascular adhesion molecules by 2 pathways; both IKK and RSK lead to phosphorylation of the p65 subunit of NF-B to increase vascular cell adhesion molecule-1 transcription. The 2 pathways are functionally important because inhibiting IKK and RSK in vascular smooth muscle cells blocks Ang II–induced expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 to limit vascular inflammation.

Key Words: angiotension II • cell signaling • nuclear factor B

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