Journal of Cardiobiology
Research Article
Cell Permeable Protein Kinase C Epsilon Peptide Inhibitor Mitigates Myocardial Ischemic- Reperfusion Injury
Nair A1, Tanoh DB1, Singh S2, Dean T2, Harrell K2, Melnik J2, Stinson C2, Le MA2, Humayun A2, Talukder Z2, Gazaway A3, Bryant A3, Chen Q2, Barsotti R2 and Young L1,2*
1Young Therapeutics, LLC, Philadelphia, PA, USA
2Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA
3Veranex, Atlanta, GA, USA
2Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA
3Veranex, Atlanta, GA, USA
*Address for Correspondence:Lindon Young, Young Therapeutics, LLC, 4170 City Avenue,
Philadelphia, PA, USA 19131; Telephone: 267 918 9373; Fax: 215 871 6869 Email Id: lindonyo@pcom.edu
Submission:26 November, 2024
Accepted:20 December, 2024
Published:27 December, 2024
Copyright: © 2024 Nair A, et al. This is an open access article distributed
under the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.
Keywords:ATP-sensitive Mitochondrial Potassium Channels;
Uncoupled Endothelial Nitric Oxide Synthase; Reactive oxygen
species; Drug conjugation; Myocardial infarction (MI)
Abstract
Percutaneous coronary intervention is the primary treatment for
acute myocardial infarction (MI). Paradoxically, restoration of blood
flow causes myocardial ischemia reperfusion (MIR) injury, principally
due to the generation of reactive oxygen species (ROS). Protein Kinase
C epsilon (PKCε) is known to play a key role in ROS production. Our PKCε
inhibitor conjugated to myristic acid (Myr), YT-001, has shown efficacy
in reducing MIR injury in both ex vivo and in vivo animal models.
This study aims to evaluate the cardioprotective effects of a dualconjugated version of our PKCε inhibitor conjugated to Myr and a Transactivator of transcription (Tat), N-Myr-Tat-PKCε (YT-002), in ex vivo rat and in vivo porcine models of MIR injury.
Ex vivo rat hearts were subjected to 30 minutes of global ischemia followed by 50 minutes of reperfusion. In vivo porcine hearts underwent 1 hour of regional ischemia followed by 3 hours of reperfusion. YT-002, or a scrambled peptide control of YT-002, or a saline control was administered at reperfusion onset. Cardiac parameters were measured throughout reperfusion and infarct size was assessed postmortem.
In the ex vivo model, YT-002 (100nM) significantly decreased infarct size to 9.3±1.8%, (n=5, p<0.01) compared to saline control (23.4±3.3%, n=5) and significantly improved left ventricular function compared to saline and scrambled YT-002.
In the in vivo model, YT-002 (0.2mg/kg) significantly restored ejection fraction at the end of reperfusion (59.4±1.2%) to the baseline (59.4±0.8%, n=3, p=0.50) and reduced infarct size (10.0±2%, n=4) compared to scrambled YT-002 (29±9%, n=3; p<0.05).
These findings indicate that YT-002 can reduce cardiac infarct size and preserve cardiac function after MI. Since heart failure can correlate with infarct size, decrease MI-induced damage to the heart has the potential to decrease the severity of heart failure thus improving patient outcomes post-MI.
This study aims to evaluate the cardioprotective effects of a dualconjugated version of our PKCε inhibitor conjugated to Myr and a Transactivator of transcription (Tat), N-Myr-Tat-PKCε (YT-002), in ex vivo rat and in vivo porcine models of MIR injury.
Ex vivo rat hearts were subjected to 30 minutes of global ischemia followed by 50 minutes of reperfusion. In vivo porcine hearts underwent 1 hour of regional ischemia followed by 3 hours of reperfusion. YT-002, or a scrambled peptide control of YT-002, or a saline control was administered at reperfusion onset. Cardiac parameters were measured throughout reperfusion and infarct size was assessed postmortem.
In the ex vivo model, YT-002 (100nM) significantly decreased infarct size to 9.3±1.8%, (n=5, p<0.01) compared to saline control (23.4±3.3%, n=5) and significantly improved left ventricular function compared to saline and scrambled YT-002.
In the in vivo model, YT-002 (0.2mg/kg) significantly restored ejection fraction at the end of reperfusion (59.4±1.2%) to the baseline (59.4±0.8%, n=3, p=0.50) and reduced infarct size (10.0±2%, n=4) compared to scrambled YT-002 (29±9%, n=3; p<0.05).
These findings indicate that YT-002 can reduce cardiac infarct size and preserve cardiac function after MI. Since heart failure can correlate with infarct size, decrease MI-induced damage to the heart has the potential to decrease the severity of heart failure thus improving patient outcomes post-MI.
Abbreviations:
Area at risk (AR); Area of necrosis (AN); Cardiac output (CO);
Calcium (Ca2+); Diacylglycerol (DAG); Dihydrobiopterin (BH2);
Ejection Fraction (EF); Endothelial-derived nitric oxide (eNOS);
Intravenously (IV); Ischemia reperfusion (I/R); Left anterior
descending (LAD); Left ventricular developed pressure (LVDP); Left
ventricular end-diastolic pressure (LVEDP); Left ventricular enddiastolic
volume (LVEDV); Left ventricular end-systolic pressure
(LVESP); Left ventricular end-systolic volume (LVESV); Maximal
rate of decrease in left ventricular pressure (dP/dtmin); Maximal rate of
increase in left ventricular pressure (dP/dtmax)., Myocardial infarction
(MI); Myocardial Ischemia Reperfusion (MIR); Myristic acid (Myr)
Myr-PKCε inhibitor (YT-001); Myr-Tat-PKCε inhibitor (YT-002);
Nitric Oxide (NO); Protein Kinase C (PKC); Protein Kinase C Epsilon
(PKCε); Pulmonary capillary wedge pressure (PCWP); Reactive
Oxygen Species (ROS); Receptor for activated C kinase 1 (RACK1)
Superoxide (SO); Tetrahydrobiopterin (BH4); Transactivator of
transcription (Tat); Tumor Necrosis Factor Alpha (TNFa).