Reduction of PKCbetaII 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 betaII isoform have yet to be discovered in this setting. Our previous findings demonstrated significantly increased PKCbetaII in the membrane fraction of injured femoral arteries in wild type (WT) mice and revealed reduction of neointimal expansion in PKCbeta(-/-) mice after acute vascular injury. As PKCbeta(-/-) mice are globally devoid of PKCbeta, we established novel transgenic (Tg) mice to test the hypothesis that the action of PKCbetaII specifically in smooth muscle cells (SMCs) mediates the formation of neointimal lesions in response to arterial injury.

METHODS

Tg mice expressing SM22alpha promoter-targeted mouse carboxyl-terminal deletion mutant PKCbetaII 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 PKCbetaII in neointimal expansion.

RESULTS

In vivo and in vitro analyses demonstrated that PKCbetaII 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 PKCbetaII in neointimal expansion in response to acute arterial injury, and suggest that targeted inactivation of PKCbetaII may be beneficial in limiting restenosis via suppression of the neointima-mediating effects of Egr-1 and MMP-9.