A New Cellular Signaling Mechanism for Angiotensin II Activation of NF-κB

Objective— Angiotensin II (Ang II) promotes vascular inflammation and remodeling via activation of nuclear factor κB (NF-κB)–mediated transcription of proinflammatory genes such as interleukin-6 (IL-6). We examined the signaling mechanism whereby Ang II activates NF-κB in vascular smooth muscle cells (VSMCs). Methods and Results— Ang II treatment did not increase phosphorylation of inhibitor of κBα (IκBα) or IκBβ 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-κB promoter activity, NF-κB 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 inter...