Published online before print March 31, 2005, doi: 10.1161/01.ATV.0000164624.00099.e7
© 2005 American Heart Association, Inc.
Vascular Biology |
A New Cellular Signaling Mechanism for Angiotensin II Activation of NF-
B
An I
B–Independent, RSK–Mediated Phosphorylation of p65
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.
Correspondence to Jie Du, Department of Internal Medicine, 9.138 Medical Research Building, 301 University Blvd, University of Texas Medical Branch, Galveston, TX 77555-1064. 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 IBß 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 VSMCs 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.
We examined an intracellular mechanism whereby Ang II activates NF-B. Ang II caused no significant increase in IB phosphorylation or protein levels. Instead, we found a nonclassical signaling pathway, Ras/MEK1/ERK/RSK, that activated NF-B via phosphorylation of p65, leading to IL-6 production and suggesting a mechanism by which Ang II causes vascular inflammation.
Key Words: angiotensin II • signaling pathway • NF-B • MAP kinase • inflammation
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