TCT-590 Mitigating Myocardial Reperfusion Injury in Coronary Revascularization: The Role of Protein Kinase C Epsilon Peptide Inhibitor

Background: Prompt coronary reperfusion is the mainstay therapy for ST-elevation myocardial infarction, significantly reducing short-term mortality. Hosever, its impact on heart failure (HF) development is a matter of ongoing debate. Infarct size correlates with mortality and HF hospitalizations. Recent studies suggest more research to reduce reperfusion injury, aiming to decrease infarct size and mitigate HF. Protein kinase C epsilon (PKCε) signaling generates reactive oxygen species (ROS) during reperfusion. This study explores the role of PKCε peptide inhibitor (PKCε-) in rat (ex vivo) and porcine (in vivo) myocardial ischemia reperfusion models, conjugated with Myr-Tat, hypothesizing PKCε- will mitigate ROS-induced reperfusion injury in both models. Methods: Ex vivo, male Sprague-Dawley rat hearts (∼300 g) were subjected to 30 minutes of global ischemia followed by 50 minutes of reperfusion. Myr-Tat-PKCε- or scrambled PKCε- (10 μmol/L to 100 pmol, n = 3-6/group) was administered during the initial 5 minutes of reperfusion. Infarct size was assessed using 1% 2,3,5-triphenyltetrazolium chloride staining. Statistical analysis was performed using the Fisher protected least significance difference test. In vivo, male Yorkshire pigs (35-50 kg) underwent 1 hour of regional ischemia followed by 3 hours of reperfusion. At reperfusion, either myr-Tat-PKCε- (n = 4, 0.2 mg/kg) or scrambled PKCε- (n = 3, 0.2 mg/kg) was given via an intra-arterial bolus. Ejection fraction was calculated, and infarct size was assessed using Evans blue dye and 1% 2,3,5-triphenyltetrazolium chloride staining. Statistical analysis was performed using Student’s t-test. Results: Ex vivo, Myr-Tat-PKCε- (4.5-10 ± 2%, n = 4-6) significantly reduced infarct size compared to untreated controls (23.5 ± 3%; n = 5; P < 0.05). Scrambled PKCε- showed no significant difference compared to untreated controls (15-19 ± 3%; n = 3-5). In vivo, Myr-Tat-PKCε- significantly restored EF to baseline levels (59 ± 1%, n = 5; P < 0.05) by the third hour of reperfusion and reduced infarct size to 10.0 ± 2% (n = 4) compared to the control (29 ± 9%, n = 3; P < 0.05). Conclusion: The findings from our study suggest that Myr-Tat-PKCε-, when administered at the beginning of reperfusion, may reduce ROS and infarct size and subsequently reduce incident post–myocardial infarction HF. Categories: CORONARY: Pharmacology/Pharmacotherapy.