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Down-Regulation of Protein Kinase C Inhibits Insulin-Like Growth Factor I-Induced Vascular Smooth Muscle Cell Proliferation, Migration, and Gene Expression¹

Department of Biology (K.Y., J.R.B., M.B.L., C.D.), University of Michigan, Natural Science Building, Ann Arbor, Michigan 48109; and Department of Medicine, University of North Carolina (D.R.C)., Chapel Hill, North Carolina 27599

Address all correspondence and requests for reprints to: Cunming Duan, Ph.D., Department of Biology, The University of Michigan, Natural Science Building, Ann Arbor, Michigan 48109-1048. E-mail: cduan{at}umich.edu

Insulin-like growth factor-I (IGF-I) plays an important role in regulating vascular smooth muscle cell (VSMC) proliferation, directed migration, differentiation, and apoptosis. The signaling mechanisms used by IGF-I to elicit these actions, however, are not well defined. In this study, we examined the role(s) of protein kinase C (PKC) in mediating the IGF-I actions in cultured porcine VSMCs. Out of the eleven known members of PKC family, PKC-, -ßI, -, -, -, , and -, were detectable by Western immunoblot analysis in these cells. Further analysis indicated that the subcellular distribution of several PKC isoforms is regulated by IGF-I. While IGF-I stimulated membrane translocation of PKC-, -, and - and regulated the cytosolic levels of PKC-ßI, it had no such effect on PKC- and -. To examine whether PKC activation is required for the IGF-I-regulated biological responses, phorbol myristate acetate (PMA) and GF109203X were used to down-regulate or inhibit PKC activity. Both PMA (1 µM) and GF109203X (20 µM) nearly completely suppressed the total PKC activity after a 30-min incubation (> 90%), and this inhibition lasted for at least 24 h. Down-regulation or inhibition of PKC activity abolished the IGF-I-induced DNA synthesis, migration and IGFBP-5 gene expression. In contrast, the IGFBP-5 expression induced by forskolin was unaffected by PKC down-regulation or inhibition, suggesting that PKC activation is required for the IGF-regulated but not the cAMP-regulated events. Because the actions of IGF-I on DNA synthesis and IGFBP-5 gene expression in VSMCs have been shown to be mediated through the phosphatidylinositol 3-kinase (PI3 kinase) signaling pathway in porcine VSMCs, the potential role of PKC in IGF-I-induced activation of PI3 kinase and PKB/Akt were examined. Treatment with either PMA or GF109203X did not significantly affect the effects of IGF-I on PI3 kinase activation or PKB/Akt phosphorylation. These results indicated that PKC-ßI, -, -, and - may play an essential role(s) in IGF-I regulation of VSMC migration, DNA synthesis and gene expression, and that these PKC isoforms may either act independently of the PI3 kinase pathway or act further downstream of PKB/Akt in the IGF signaling network.

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