Abstract 4748: 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 (ΨϵRACK), 3mM ϵPKC inhibitor (ϵV1–2), the carrier control (TAT47–57), 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). [figure1] 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.