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Am J Physiol Cell Physiol 290: C1583-C1591, 2006. First published January 25, 2006; doi:10.1152/ajpcell.00390.2005
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VASCULAR BIOLOGY

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

Roman Ginnan, Benjamin J. Guikema, Harold A. Singer, and David Jourd'heuil

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-1beta (IL-beta) is an important regulator of gene expression in vascular smooth muscle (VSM), the signal transduction pathways leading to transcriptional activation upon IL-1beta stimulation are poorly understood. Recent studies have implicated IL-1beta-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)-{delta}-dependent manner utilizing a signaling mechanism independent of p21ras (Ras) and Raf1 activation. Stimulation of rat aortic VSM cells with IL-1beta activated PLC-{gamma} and pharmacological inhibition of PLC attenuated IL-1beta-induced ERK1/2 activation and subsequent iNOS expression. Stimulation with IL-1beta activated PKC-{alpha} and -{delta}, which was blocked using the PLC inhibitor U-73122. Pharmacological studies using isoform-specific PKC inhibitors and adenoviral overexpression of constitutively active PKC-{delta} indicated that ERK1/2 activation was PKC-{alpha} independent and PKC-{delta} dependent. Similarly, adenoviral overexpression of constitutively activated PKC-{delta} enhanced iNOS expression. IL-1beta 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-{delta} as a critical component of the IL-1-dependent activation of ERK in VSM cells.

nitric oxide synthase



Address for reprint requests and other correspondence: R. Ginnan, Center for Cardiovascular Sciences, MC-8, Albany Medical College, Albany, NY 12208 (e-mail: ginnanr{at}mail.amc.edu)




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