Protein Kinase C Isoform (PKC) Peptide Activator/Inhibitors Exert Cardioprotective Effects in Polymorphonuclear Leukocyte (PMN)-induced Ischemia/Reperfusion (I/R) Injury

Abstract

Introduction Myocardial I/R injury is characterized by endothelial dysfunction, enhanced PMN infiltration into the myocardium, that results in sustained cardiac contractile dysfunction [1,2]. Enhancement of endothelial basal nitric oxide (NO) release or inhibition of PMN superoxide (SO) release reduces endothelial dysfunction and attenuates PMN/endothelial interaction. PKC is a key enzyme that regulates endothelial NO release and PMN SO release [1,2]. However, selective PKC isoforms mediating these responses are not well understood. Myristoylated PKC isoform peptides (MW=1130 to1928; Genemed Synthesis, Inc.) penetrate into cells by simple diffusion. The PKC beta II (βII) (N-MyrSLNPEWNET) and delta (δ) isoform (N-Myr-HDAPIGYD) inhibitors bind to its receptor-activated C kinase region attenuating PKC translocation. By contrast, the PKC δ peptide activator (N-Myr-MRAAEDPM) augments translocation. The PKC zeta (ζ) peptide inhibitor (N-Myr-SIYRRGARRWRKL) binds to the pseudosubstrate domain, attenuating interaction with cell membrane substrates, eNOS and NADPH oxidase [1,2]. We hypothesized that selective PKC peptide isoforms would attenuate PMNinduced contractile dysfunction (i.e., left ventricular developed pressure; LVDP) after I/R when given separately or in combination (i.e., βII /ζ) during reperfusion in the isolated perfused rat heart. We also wanted to determine the mechanism of action to account for any potential cardioprotective effects following I/R.