Presentation
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
Experimental Biology 2018
(2018)
Abstract
Protein kinase C epsilon (PKCϵ) activation is thought to be central in mediating cardioprotection conferred by myocardial ischemic preconditioning. PKCϵ activation via PKCϵ activator peptide (PKCϵ+, HDAPIGYD, MW= 887 g/mol) as pretreatment (PT) is a pharmacological means to mimic preconditioning. However, unconjugated or native PKCϵ+ requires the use of cell permeabilization methods for efficacious intracellular targeting to improve cardiac function and reduce necrotic cell death. Therefore, conjugating PKCϵ+ to known intracellular delivery moieties may be a method to effectively activate PKCϵ for cardioprotection. To test this hypothesis, we subjected isolated perfused rat hearts to PT with PKCϵ+ 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 PKCϵ+ PT (10mM, n=5) and untreated control hearts (n=6). We found that compared to control hearts, PT with Myr-PKCϵ+ and TAT-PKCϵ+ 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 PKCϵ+ showed almost no change in infarct size compared to controls, 41±3% versus 35±2%. Both myristic acid- and TAT-conjugated PKCϵ+ PT hearts restored post-reperfused left ventricular developed pressure (LVDP) to 52±5% and 50±10% compared to both native PKCϵ+ 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 PKCϵ+ 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 PKCϵ+ may be an effective treatment to attenuate cell death in coronary bypass or organ transplantation settings.
Disciplines
Publication Date
April, 2018
Location
San Diego, CA
DOI
https://www.fasebj.org/doi/10.1096/fasebj.2018.32.1_supplement.717.25
Citation Information
Anahi McIntyre, Hanna Kim, Matthew Finnegan, Kevin Amuquandoh, et al.. "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" Experimental Biology 2018 (2018) Available at: http://works.bepress.com/lindon_young/62/