Reduction of PKCβII activity in smooth muscle cells attenuates acute arterial injury

Objective: The ubiquitous enzyme Protein Kinase C (PKC) has been linked to the pathogenesis of vascular injury, but the cell-specific and discrete functions of the beta II isoform have yet to be discovered in this setting. Our previous findings demonstrated significantly increased PKC beta II in the membrane fraction of injured femoral arteries in wild type (WT) mice and revealed reduction of neointimal expansion in PKC beta(-/-) mice after acute vascular injury. As PKC beta(-/-) mice are globally devoid of PKC beta, we established novel transgenic (Tg) mice to test the hypothesis that the action of PKC beta II specifically in smooth muscle cells (SMCs) mediates the formation of neointimal lesions in response to arterial injury. Methods: Tg mice expressing SM22 alpha promoter-targeted mouse carboxyl-terminal deletion mutant PKC beta II were produced using standard techniques, subjected to femoral artery injury and compared with littermate controls. Smooth muscle cells (SMCs) were isolated from wild type (WT) and Tg mice and exposed to a prototypic stimulus, tumor necrosis factor (TNF)-alpha. Multiple strategies were employed in vivo and in vitro to examine the molecular mechanisms underlying the specific effects of SMC PKC beta II in neointimal expansion. Results: In vivo and in vitro analyses demonstrated that PKC beta II activity in SMCs was critical for neointimal expansion in response to arterial injury, at least in part via regulation of ERK1/2, Egr-1 and induction of MMP-9. Conclusions: These data identify the SMC-specific regulatory role of PKC beta II in neointimal expansion in response to acute arterial injury, and suggest that targeted inactivation of PKC beta II may be beneficial in limiting restenosis via suppression of the neointima-mediating effects of Egr-1 and MMP-9. (C) 2010 Elsevier Ireland Ltd. All rights reserved.