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VASCULAR BIOLOGY

PKC- mediates activation of ERK1/2 and induction of iNOS by IL-1 in vascular smooth muscle cells

Center for Cardiovascular Sciences, Albany Medical College, Albany, New York

Submitted 2 August 2005 ; accepted in final form 19 January 2006

Although the inflammatory cytokine interleukin-1 (IL-) is an important regulator of gene expression in vascular smooth muscle (VSM), the signal transduction pathways leading to transcriptional activation upon IL-1 stimulation are poorly understood. Recent studies have implicated IL-1-mediated ERK1/2 activation in the upregulation of type II nitric oxide synthase (iNOS) in VSM. We report that these events are mediated in a phospholipase C (PLC)- and protein kinase C (PKC)--dependent manner utilizing a signaling mechanism independent of p21^ras (Ras) and Raf1 activation. Stimulation of rat aortic VSM cells with IL-1 activated PLC- and pharmacological inhibition of PLC attenuated IL-1-induced ERK1/2 activation and subsequent iNOS expression. Stimulation with IL-1 activated PKC- and -, which was blocked using the PLC inhibitor U-73122. Pharmacological studies using isoform-specific PKC inhibitors and adenoviral overexpression of constitutively active PKC- indicated that ERK1/2 activation was PKC- independent and PKC- dependent. Similarly, adenoviral overexpression of constitutively activated PKC- enhanced iNOS expression. IL-1 stimulation did not induce either Ras or Raf1 activity. The absence of a functional role for Ras and Raf1 related to ERK1/2 activation and iNOS expression was further confirmed by adenoviral overexpression of dominant-negative Ras and treatment with the Raf1 inhibitor GW5074. Taken together, we have outlined a novel transduction pathway implicating PKC- as a critical component of the IL-1-dependent activation of ERK in VSM cells.

nitric oxide synthase

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