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TRANSLATIONAL PHYSIOLOGY

PKC--dependent pathways contribute to PDGF-stimulated ERK1/2 activation in vascular smooth muscle

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

Submitted 12 October 2004 ; accepted in final form 18 January 2005

ABSTRACT

Platelet-derived growth factor (PDGF) is an important regulator of vascular smooth muscle (VSM) cell growth and migration and has been identified as a key mediator of neointima formation resulting from vascular injury. PDGF exerts its effects, in part, through activation of ERK1/2. Previously, we reported that PKC-, specifically compared with PKC-, mediated phorbol ester- and ATP-dependent activation of ERK1/2 in VSM cells. The purpose of this study was to determine whether PKC- was involved in PDGF-dependent activation of ERK1/2 in VSM cells. The addition of PDGF resulted in the activation, and Src family kinase-dependent tyrosine phosphorylation, of PKC-. Treatment with rottlerin (0.1–10 µM), a selective PKC- inhibitor, or adenoviral overexpression of kinase-negative PKC- significantly attenuated PDGF-induced activation of ERK1/2. The effects of the PKC- inhibitors decreased with increasing concentrations of activator PDGF. Interestingly, treatment with Gö6976 (0.1–3 µM), a selective inhibitor of cPKCs, or adenoviral overexpression of kinase-negative PKC- also inhibited PDGF-stimulated ERK1/2. Furthermore, inhibition of cPKC activity with Gö6976 or overexpression of kinase-negative PKC- attenuated PKC- activation and tyrosine phosphorylation in response to PDGF. These studies indicate involvement of both PKC- and PKC- isozymes in PDGF-stimulated signaling in VSM and suggest an unexpected role for PKC- in the regulation of PKC- activity.

phospholipase C-; protein kinase C-; protein kinase C-

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