title: Dual pathways for nuclear factor kappaB activation by angiotensin II in vascular smooth muscle: phosphorylation of p65 by IkappaB kinase and ribosomal kinase.
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.
authors.affiliation: Department of Medicine-Nephrology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Jizhong
authors.initials: J
authors.lastname: Cheng
authors.forename: Yewei
authors.initials: Y
authors.lastname: Ma
authors.forename: Walter
authors.initials: W
authors.lastname: Thomas
authors.forename: Jiqiang
authors.initials: J
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D051550:I-kappa B Kinase / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D019893:Ribosomal Protein S6 Kinases; D051550:I-kappa B Kinase; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse