Abstract 12549: PKCdelta-Deficiency Accelerates Neointimal Lesions in a Mouse Model of Vascular Injury Involving Delayed Reendothelialization and Vasohibin-1 Accumulation
Background: Protein kinase C (PKC) delta functions as a signal transducer mediating several essential functions of cell proliferation and apoptosis. However, the effect of PKCdelta on neointimal formation is currently unknown. In the present study, we used a vascular injury model in PKCdelta knockout mice to investigate the role of PKCdelta in the lesion development and underlying mechanism.
Methods and Results: Three weeks after wire injury of femoral arteries, neointimal lesions were significantly increased in PKCdelta −/− mice compared with wild-type animals. Immunohistochemical staining revealed that total numbers of smooth muscle cells and macrophages in the lesions were markedly elevated without the alterations of the ratio between these two types of cells. To further study the mechanisms of PKCdelta -mediated increase in the lesion, in vivo endothelial migration model was established to evaluate endothelial wound healing after wire injury. Data indicate that reendothelialization of the injured vessel was markedly delayed in PKCdelta−/− mice that coincided with more severe intimal hyperplasia. When endothelial cells were cultivated from cardiac tissues of PKCdelta−/− and PKCdelta+/+ mice, the ability of cell migration was significantly reduced in PKCdelta−/− mice, but no difference in proliferation and apoptosis were found. These altered endothelial migration was also verified by using PKCdelta inhibitor and siRNA techniques in wild-type cells. Interestingly, vasohibin-1, an anti-migration protein, was elevated in endothelial cells derived from PKCdelta deficient mice, which was identified largely due to delayed protein degradation mediated by PKCdelta. Downregulation of vasohibin-1restored the migration rate of PKCdelta−/− endothelial cells to the level similar to wild-type cells.
Conclusions: Our data provide the first evidence that PKCdelta-enhanced neointima formation is mainly due to delayed reendothelialization, which is mediated by increased cellular vasohibin-1 that is regulated by PKCdelta.
- © 2010 by American Heart Association, Inc.