Protein kinase C delta induces apoptosis of vascular smooth muscle cells through induction of the tumor suppressor p53 by both p38-dependent and p38-independent mechanisms

Abstract

Apoptotic death of vascular smooth muscle cells (SMCs) is a prominent feature of blood vessel remodeling. In the present study, we examined the novel PKC isoform protein kinase C delta (PKC5) and its role in vascular SMC apoptosis. In A10 SMCs, overexpression of PKCδ was sufficient to induce apoptosis, whereas inhibition of PKCδ diminished H2O 2-induced apoptosis. Moreover, evidence is provided that the tumor suppressor p53 is an essential mediator of PKCδ-induced apoptosis in SMCs. Activation of PKCδ led to accumulation as well as phosphorylation of p53 in SMCs; this induction correlated with apoptosis. Furthermore, blocking p53 induction with small interference RNA or targeted gene deletion prevented PKCδ-induced apoptosis, whereas restoring p53 expression rescued the ability of PKCδ to induce apoptosis in p53 null SMCs. We also establish that PKCδ regulates p53 at both transcriptional and post-translational levels. Specifically, the transcriptional regulation required p38 MAPK, whereas the post-translational modification, at least for serine 46, did not involve MAPK. Additionally, PKCδ, p38 MAPK, and p53 co-associate in cells under conditions favoring apoptosis. Together, our data suggest that SMC apoptosis proceeds through a pathway that involves PKCδ, the intermediary p38 MAPK, and the downstream target tumor suppressor p53. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.