Article

A new cellular signaling mechanism for angiotensin II activation of NF-kappaB: An IkappaB-independent, RSK-mediated phosphorylation of p65.

Department of Internal Medicine, The University of Texas Medical Branch, Galveston 77555-1064, USA.
Arteriosclerosis Thrombosis and Vascular Biology (impact factor: 6.37). 07/2005; 25(6):1148-53. DOI:10.1161/01.ATV.0000164624.00099.e7 pp.1148-53
Source: PubMed

ABSTRACT Angiotensin II (Ang II) promotes vascular inflammation and remodeling via activation of nuclear factor kappaB (NF-kappaB)-mediated transcription of proinflammatory genes such as interleukin-6 (IL-6). We examined the signaling mechanism whereby Ang II activates NF-kappaB in vascular smooth muscle cells (VSMCs).
Ang II treatment did not increase phosphorylation of inhibitor of kappaBalpha (IkappaBalpha) or IkappaBbeta 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-kappaB promoter activity, NF-kappaB 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-kappaB and p65 phosphorylation. Immunopurified RSK from Ang II-treated VSMCs phosphorylated recombinant glutathione S-transferase-p65 in vitro.
We uncovered a nonclassical signaling pathway (Ras/MEK1/ERK/RSK) from Ang II to activation of NF-kappaB, a mechanism by which Ang II stimulates RSK-mediated phosphorylation of p65 to participate in vascular inflammation.

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Keywords

Ang II
 
Ang II activation
 
Ang II treatment
 
Ang II-induced activation
 
Ang II-treated VSMCs phosphorylated recombinant glutathione S-transferase-p65
 
Angiotensin II
 
dominant-negative MEK1 adenovirus
 
extracellular signal-regulated kinase
 
IL-6 transcription/production
 
MEK1 suppressed
 
mitogen-activated protein kinase kinase-1
 
NF-kappaB DNA-binding activity
 
NF-kappaB)-mediated transcription
 
nonclassical signaling pathway
 
nuclear factor kappaB
 
proinflammatory genes
 
Ras/MEK1/ERK/RSK
 
ribosomal S6 kinase
 
vascular inflammation
 
vascular smooth muscle cells