Abstract 13618: Sustained Inhibition of Epsilon Protein Kinase C Inhibits Vascular Restenosis After Balloon Injury and Stenting
Background: εPKC 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 εPKC 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 εPKC activator ΨεRACK, the selective εPKC inhibitor εV1-2, or saline. Both down-stream cascades of the PDGF receptor via ERK 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 ΨεRACK significantly promoted neointima development (32.4±4.9%, p=0.033), whereas εV1-2 significantly inhibited luminal narrowing (9.2±4.3%, p=0.039). εPKC inhibition led to significantly reduced VSMC ERK phosphorylation in vivo, whereas Akt phosphorylation was not markedly affected. Neointimal proliferation in vivo and PDGF-induced VSMC proliferation/ migration in vitro were significantly inhibited by εV1−2. The inhibition of the PDGF pathway was mediated by inhibiting down-stream ERK and Akt phosphorylation. In vitro, εV1-2 showed inhibitory properties on EC proliferation, but that did not prevent reendothelialization in vivo. εV1-2 showed proapoptotic effects on VSMC in vitro. After stent implantation, luminal restenosis (quantified by optical coherence tomography imaging) was significantly reduced with εV1-2 (8.0±2.0%) compared to saline (20.2±9.8%, p=0.028).
Conclusions:εPKC seems to be centrally involved in the development of neointimal hyperplasia. We suggest that εPKC inhibition may be mediated via inhibition of ERK and Akt activation. εPKC modulation may become a new therapeutic target against vascular restenosis
- © 2010 by American Heart Association, Inc.