{'fraction_non_alphanumeric': 0.044596223382884694, 'fraction_numerical': 0.022900763358778626, 'mean_word_length': 5.859504132231405, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Comparing the Efficacy of Pharmacological Preconditioning with Myristic Acid‐conjugated, TAT‐ conjugated and Native Protein Kinase C Epsilon Peptide Activator in Myocardial Ischemia/Reperfusion (MI/R) Models

Protein kinase C epsilon (PKCɛ) activation is thought to be central in mediating cardioprotection conferred by myocardial ischemic preconditioning. PKCɛ activation via PKCɛ activator peptide (PKCɛ+, HDAPIGYD, MW= 887 g/mol) as pretreatment (PT) is a pharmacological means to mimic preconditioning. However, unconjugated or native PKCɛ+ requires the use of cell permeabilization methods for efficacious intracellular targeting to improve cardiac function and reduce necrotic cell death. Therefore, conjugating PKCɛ+ to known intracellular delivery moieties may be a method to effectively activate PKCɛ for cardioprotection. To test this hypothesis, we subjected isolated perfused rat hearts to PT with PKCɛ+ conjugated to either myristic acid (Myr‐HDAPIGYD, MW= 1097 g/mol, 10mM, n=5) or transactivating (TAT) carrier peptide (YGRKKRRQRRR‐CC‐HDAPIGYD, MW= 2632 g/mol, 10mM, n=6) to evaluate the efficacy of these intracellularly targeted peptide analogs in attenuating contractile dysfunction and infarct size after MI (30 min)/R (90 min) in comparison with native PKCɛ+ PT (10mM, n=5) and untreated control hearts (n=6). We found that compared to control hearts, PT with Myr‐PKCɛ+ and TAT‐PKCɛ+ significantly reduced infarct size from 41±3% to 29 ±1% and 28±2% (p<0.05) respectively compared to control hearts assessed by 1% triphenyltetrazolium chloride staining of heart tissue. By contrast, hearts PT with native PKCɛ+ showed almost no change in infarct size compared to controls, 41±3% versus 35±2%. Both myristic acid‐ and TAT‐conjugated PKCɛ+ PT hearts restored post‐reperfused left ventricular developed pressure (LVDP) to 52±5% and 50±10% compared to both native PKCɛ+ PT and control hearts which only recovered to 33±9% and 38±4% of initial baseline values respectively, but this improvement was not statistically significant. These preliminary results indicate that increasing cellular permeability of PKCɛ+ via conjugation to either myristic acid or TAT significantly improved its efficaciousness in attenuating infarct size when given before ischemia as a pharmacologic mimic of ischemic preconditioning. These results suggest that Myr‐ or TAT‐conjugated PKCɛ+ may be an effective treatment to attenuate cell death in coronary bypass or organ transplantation settings.