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

Arterioscler Thromb Vasc Biol. 2005 Jun;25(6):1148-53. doi: 10.1161/01.ATV.0000164624.00099.e7. Epub 2005 Mar 31.


Objective: 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).

Methods and results: 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.

Conclusions: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin II / pharmacology
  • Animals
  • Aorta, Thoracic / cytology
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • MAP Kinase Kinase 1 / metabolism
  • Male
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Phosphorylation / drug effects
  • RNA, Small Interfering
  • Rats
  • Rats, Sprague-Dawley
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Transcription Factor RelA / metabolism*
  • Vasculitis / metabolism*
  • Vasoconstrictor Agents / pharmacology
  • ras Proteins / metabolism


  • RNA, Small Interfering
  • Transcription Factor RelA
  • Vasoconstrictor Agents
  • Angiotensin II
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, rat
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1
  • ras Proteins