on March 31, 2005
Published online before print March 31, 2005, doi: 10.1161/01.ATV.0000164624.00099.e7
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Submitted on January 10, 2005
Accepted on March 21, 2005
A New Cellular Signaling Mechanism for Angiotensin II Activation of NF-
B. An IB-Independent, RSK-Mediated Phosphorylation of p65
Liping Zhang ;
From the Departments of Internal Medicine (L.Z., Y.M., J.Z., J.C., J.D.) and Human Biological Chemistry and Genetics (J.D.), The University of Texas Medical Branch, Galveston.
* To whom correspondence should be addressed. E-mail: jidu{at}utmb.edu.
Objective--Angiotensin II (Ang II) promotes vascular inflammation and remodeling via activation of nuclear factor 
B (NF-B)-mediated transcription of proinflammatory genes such as interleukin-6 (IL-6). We examined the signaling mechanism whereby Ang II activates NF-B in vascular smooth muscle cells (VSMCs).
Methods and Results--Ang II treatment did not increase phosphorylation of inhibitor of B
(IB) or IB
or decrease their levels. In contrast, mitogen-activated protein kinase kinase-1 (MEK1) inhibition (dominant-negative MEK1 adenovirus or inhibitor U0126) suppressed Ang II-induced NF-B promoter activity, NF-B DNA-binding activity, p65 phosphorylation, and led to 70% reduction in IL-6 transcription/production. The mechanism involved Ang II activation of Ras and MEK1. Signaling distal to MEK1 involved extracellular signal-regulated kinase (ERK) because inhibition of MEK1 suppressed the Ang II-induced activation of ribosomal S6 kinase (RSK), a substrate of ERK. Downregulation of RSK by small interfering RNA (SiRNA) in VSCMs was found to suppress Ang II-induced activation of NF-B and p65 phosphorylation. Immunopurified RSK from Ang II-treated VSMCs phosphorylated recombinant glutathione S-transferase-p65 in vitro.
Conclusion--We uncovered a nonclassical signaling pathway (Ras/MEK1/ERK/RSK) from Ang II to activation of NF-B, a mechanism by which Ang II stimulates RSK-mediated phosphorylation of p65 to participate in vascular inflammation.
Key words: angiotensin II • signaling pathway • NF-
B •
MAP kinase •
inflammation
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