Sustained Inhibition of ε Protein Kinase C Inhibits Vascular Restenosis After Balloon Injury and Stenting

Background-epsilon Protein kinase C (epsilon PKC) is involved in vascular smooth muscle cell (VSMC) activation, but little is known about its function in vascular pathology. We aimed at assessing the role of epsilon PKC in the development of restenosis. Methods and Results-Rat models of aortic balloon injury with or without subsequent stenting were used. Rats were treated with the selective epsilon PKC activator psi epsilon receptor for activated protein kinase C (psi epsilon RACK), the selective epsilon PKC inhibitor epsilon V1-2, or saline. Both down-stream cascades of the platelet-derived growth factor receptor via extracellular signal-regulated kinase and Akt, respectively, were evaluated in vivo and in VSMC cultures. Intimal hyperplasia with luminal obliteration developed in saline-treated balloon-injured rat aortas (20.3 +/- 8.0%), and psi epsilon RACK significantly promoted neointima development (32.4 +/- 4.9%, P=0.033), whereas epsilon V1-2 significantly inhibited luminal narrowing (9.2 +/- 4.3%, P=0.039). epsilon PKC inhibition led to significantly reduced VSMC extracellular signal-regulated kinase phosphorylation in vivo, whereas Akt phosphorylation was not markedly affected. Neointimal proliferation in vivo and platelet-derived growth factor-induced VSMC proliferation/migration in vitro were significantly inhibited by epsilon V1-2. The inhibition of the platelet-derived growth factor pathway was mediated by inhibiting down-stream extracellular signal-regulated kinase and Akt phosphorylation. In vitro, epsilon V1-2 showed inhibitory properties on endothelial cell proliferation, but that did not prevent reendothelialization in vivo. epsilon V1-2 showed proapoptotic effects on VSMC in vitro. After stent implantation, lumina] restenosis (quantified by optical coherence tomography imaging) was significantly reduced with epsilon V1-2 (8.0 +/- 2.0%) compared with saline (20.2 +/- 9.8%, P=0.028). Conclusions-epsilon PKC seems to be centrally involved in the development of neointimal hyperplasia. We suggest that epsilon PKC inhibition may be mediated via inhibition of extracellular signal-regulated kinase and Akt activation. epsilon PKC modulation may become a new therapeutic target against vascular restenosis. (Circulation. 2010;122[suppl 1]:S170-S178.)