Dual pathways for nuclear factor kappaB activation by angiotensin II in vascular smooth muscle: phosphorylation of p65 by IkappaB kinase and ribosomal kinase
Authors: Liping Zhang
Walter Thomas
Jiqiang Zhang
Jizhong Cheng
Yewei Ma
Jie Du
Journal: Circulation Research (2005)
Discipline: CLINICAL MEDICINE
Keywords: NF-kappaB; Angiotensin II; IKK; RSK; Vascular adhesion molecules
Affiliations: Department of Medicine-Nephrology, Baylor College of Medicine, Houston, Texas, USA., 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.

Abstract:  Activation of nuclear factor (NF)-kappaB 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-kappaB 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-kappaB in mouse embryonic fibroblast is suppressed (approximately 70%) either by deletion of IkappaB 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 IKKbeta. Thus, Ang II also stimulates NF-kappaB via IKK. In vitro, we found that Ang II stimulates IKK to phosphorylate myelin basic protein and the p65 subunit of NF-kappaB. The mechanism by which Ang II activates IKK is to increase phosphorylation of IKKbeta in its activation loop (Ser181) rather than IkappaB phosphorylation. Inhibiting both the RSK and IKK pathways completely blocks the Ang II-induced p65 phosphorylation and NF-kappaB 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-kappaB 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. 

Retracted: Yes

PubPeer comments:
 The actin immunoblot have been reused between Fig 2A and Fig 5D, note the different treatment.  , 
 The actin panel in Fig. 4B is unexpectedly similar to the 180u00b0 Rotated actin panel in Fig. 5D  , 
 Unexpected similarity between the actin panel in Fig 5C and the vertical compressed actin panel in Fig 5F  , 
 2021 retraction. https: www.ahajournals.org doi 10.1161 RES.0000000000000460 In the article by Zhang et al, u201cDual Pathways for Nuclear Factor u03baB Activation by Angiotensin II in Vascular Smooth Muscle: Phosphorylation of p65 by Iu03baB Kinase and Ribosomal Kinase,u201d which published in the November 11, 2005 issue of the journal (Circ Res. 2005;97:975u2013982. doi: 10.1161 01.RES.0000190589.52286.41), concerns were raised about duplication of internal loading controls of multiple Western blots in Figure panels 2A, 3C, 4B, 5C, 5D, and 5F. Although the authors stand by their results and conclusion, they acknowledge the improper use of loading controls. As the original blot films are no longer available, the authors have requested to retract the article. ,