Published online before print October 13, 2005, doi: 10.1161/01.RES.0000190589.52286.41
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on March 21, 2005
Revised on September 1, 1005
Accepted on September 29, 2005
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 ;
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.
* To whom correspondence should be addressed. 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 IKK
. 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 IKK 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 MEK-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
This article has been cited by other articles:
 |
|
 |
|
  R. C. Laxton, Y. Hu, J. Duchene, F. Zhang, Z. Zhang, K.-Y. Leung, Q. Xiao, R. S. Scotland, C. P. Hodgkinson, K. Smith, et al. A Role of Matrix Metalloproteinase-8 in Atherosclerosis Circ. Res., October 23, 2009; 105(9): 921 - 929. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zhang, J. Du, Z. Hu, G. Han, P. Delafontaine, G. Garcia, and W. E. Mitch IL-6 and Serum Amyloid A Synergy Mediates Angiotensin II-Induced Muscle Wasting J. Am. Soc. Nephrol., March 1, 2009; 20(3): 604 - 612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Alexis, N. Wang, W. Che, N. Lerner-Marmarosh, A. Sahni, V. A. Korshunov, Y. Zou, B. Ding, C. Yan, B. C. Berk, et al. Bcr Kinase Activation by Angiotensin II Inhibits Peroxisome Proliferator-Activated Receptor {gamma} Transcriptional Activity in Vascular Smooth Muscle Cells Circ. Res., January 2, 2009; 104(1): 69 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Choudhary, M. Lu, R. Cui, and A. R. Brasier Involvement of a Novel Rac/RhoA Guanosine Triphosphatase-Nuclear Factor-{kappa}B Inducing Kinase Signaling Pathway Mediating Angiotensin II-Induced RelA Transactivation Mol. Endocrinol., September 1, 2007; 21(9): 2203 - 2217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Henke, R. Schmidt-Ullrich, R. Dechend, J.-K. Park, F. Qadri, M. Wellner, M. Obst, V. Gross, R. Dietz, F. C. Luft, et al. Vascular Endothelial Cell Specific NF-{kappa}B Suppression Attenuates Hypertension-Induced Renal Damage Circ. Res., August 3, 2007; 101(3): 268 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cheng and J. Du Mechanical Stretch Simulates Proliferation of Venous Smooth Muscle Cells Through Activation of the Insulin-Like Growth Factor-1 Receptor Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1744 - 1751. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Ai, Y. Fu, D. Guo, H. Tanaka, N. Wang, C. Tang, B. D. Hammock, J. Y.-J. Shyy, and Y. Zhu Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo PNAS, May 22, 2007; 104(21): 9018 - 9023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Cui, B. Tieu, A. Recinos, R. G. Tilton, and A. R. Brasier RhoA Mediates Angiotensin II-Induced Phospho-Ser536 Nuclear Factor {kappa}B/RelA Subunit Exchange on the Interleukin-6 Promoter in VSMCs Circ. Res., September 29, 2006; 99(7): 723 - 730. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Douillette, A. Bibeau-Poirier, S.-P. Gravel, J.-F. Clement, V. Chenard, P. Moreau, and M. J. Servant The Proinflammatory Actions of Angiotensin II Are Dependent on p65 Phosphorylation by the I{kappa}B Kinase Complex J. Biol. Chem., May 12, 2006; 281(19): 13275 - 13284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ma, L. Zhang, T. Peng, J. Cheng, S. Taneja, J. Zhang, P. Delafontaine, and J. Du Angiotensin II Stimulates Transcription of Insulin-Like Growth Factor I Receptor in Vascular Smooth Muscle Cells: Role of Nuclear Factor-{kappa}B Endocrinology, March 1, 2006; 147(3): 1256 - 1263. [Abstract] [Full Text] [PDF]
|
|