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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
Author(s) -
McIntyre Anahi,
Kim Hanna,
Finnegan Matthew,
Amuquandoh Kevin,
Chen Qian,
Barsotti Robert,
Young Lindon
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.717.25
Subject(s) - protein kinase c , cardioprotection , activator (genetics) , intracellular , chemistry , peptide , medicine , pharmacology , myocardial infarction , kinase , biochemistry , receptor
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. Support or Funding Information This study was supported by the Center for Chronic Disorders of Aging, the Division of Research and the Department of Bio‐Medical Sciences at Philadelphia College of Osteopathic Medicine. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .