Identifying PKC epsilon as a target molecule to control intimal hyperplasia

Background: The prevention of chronic allograft vasculopathy (CAV) after heart transplantation remains a major problem for long-term success. Epsilon protein kinase C (εPKC) is a PKC isoform that plays pivotal roles in myocardial infarction and in heart failure. Here we investigate whether PKC epsilon activation is also involved in the development of intimal hyperplasia. Methods: Rats underwent balloon denudation of the abdominal aorta and received either 3mM εPKC activator (yeRACK), 3mM εPKC inhibitor (εV1-2), the carrier control (TAT_47-57), or saline by osmotic pump at ~3mg/kg/day for 4 weeks (6 rats/group). The treatment began intraoperatively. Aortas were harvested for histologic evaluation, and luminal obliteration and intima/media ratios were analyzed using computer morphometry. Results: Histology of untreated animals revealed marked intimal hyperplasia with moderate luminal obliteration (19.9±9%). Neointima formation was significantly increased by the εPKC activator (32±5.5%; p=0.017 vs. untreated) and significantly decreased by the εPKC inhibitor (9.1± 4.3%; p=0.016 vs. untreated). No difference was observed between the untreated control and the TAT carrier peptide contol groups (p=0.43). The intima/media ratio was significantly higher in the εPKC activator group compared to the εPKC inhibitor group(0.67±0.46 and 0.25±0.46, respectively; p=0.034). Treatment with either of the εPKC regulators was very well tolerated and the animals in the εPKC activator as well as the εPKC inhibitor groups gained weight during the 4 week treatment period (105± 1.9% and 102±3.4%, respectively; p=ns). No differences in creatinine, BUN, cholesterol, triglycerides, ALT, and AST were observed between the four groups. Conclusion: These data suggest that εPKC activity contributes to the non-immunological development of intimal hyperplasia and that an εPKC-selective inhibitor, such as εV1-2, could augment current therapeutic strategies to suppress the development of vascular stenosis.