Protein Kinase Cδ Deficiency Accelerates Neointimal Lesions of Mouse Injured Artery Involving Delayed Reendothelialization and Vasohibin-1 Accumulation

Objective-To use protein kinase C (PKC) delta-knockout mice to investigate the role of PKC delta in lesion development and to understand the underlying mechanism of the vascular disease. Methods and Results-PKC delta functions as a signal transducer mediating several essential functions of cell proliferation and apoptosis. However, the effect of PKC delta on neointimal formation in wire-injured vessels is unknown. Three weeks after wire injury of femoral arteries, neointimal lesions were significantly increased in PKC delta(-/-) mice compared with PKC delta(+/+) animals. Immunohistochemical staining revealed that total numbers of smooth muscle cells and macrophages in the lesions of PKC delta(-/-) mice were markedly elevated without changing the ratio of these 2 cell types. To further elucidate the mechanisms of PKC delta-mediated increase in the lesion, an in vivo endothelial migration model was established to evaluate endothelial wound healing after wire injury. Data showed that reendothelialization of the injured vessel was markedly delayed in PKC delta(-/-) mice; this coincided with more severe intimal hyperplasia. Migration of endothelial cells cultivated from cardiac tissue was markedly reduced in the absence of PKC delta, whereas no difference in proliferation or apoptosis was detected. Inhibition of PKC delta activity or protein expression by small hairpin RNA (shRNA) in cultured endothelial cells confirmed the defective migratory phenotype. Interestingly, vasohibin-1, an antiangiogenesis protein, was elevated in endothelial cells derived from PKC delta(-/-) mice, which was mainly because of delayed protein degradation mediated by PKC delta. Downregulation of vasohibin-1 restored the migration rate of PKC delta(-/-)endothelial cells to a similar level as PKC delta(+/+) cells. Conclusion-PKC delta deficiency enhances neointimal formation, which is associated with delayed reendothelialization and involves increased cellular vasohibin-1 accumulation. (Arterioscler Thromb Vasc Biol. 2010;30:2467-2474.)