Protein kinase C-zeta inhibition exerts cardioprotective effects in ischemia-reperfusion injury.
Ischemia followed by reperfusion (I/R) in the presence of polymorphonuclear leukocytes (PMNs) results in marked cardiac contractile dysfunction. A cell-permeable PKC-zeta peptide inhibitor was used to test the hypothesis that PKC-zeta inhibition could attenuate PMN-induced cardiac contractile dysfunction by suppression of superoxide production from PMNs and increase nitric oxide (NO) release from vascular endothelium. The effects of the PKC-zeta peptide inhibitor were examined in isolated ischemic (20 min) and reperfused (45 min) rat hearts reperfused with PMNs. The PKC-zeta inhibitor (2.5 or 5 microM, n = 6) significantly attenuated PMN-induced cardiac dysfunction compared with I/R hearts (n = 6) receiving PMNs alone in left ventricular developed pressure (LVDP) and the maximal rate of LVDP (+dP/dt(max)) cardiac function indexes (P < 0.01), and these cardioprotective effects were blocked by the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (50 microM). Furthermore, the PKC-zeta inhibitor significantly increased endothelial NO release 47 +/- 2% (2.5 microM, P < 0.05) and 54 +/- 5% (5 microM, P < 0.01) over basal values from the rat aorta and significantly inhibited superoxide release from phorbol-12-myristate-13-acetate-stimulated rat PMNs by 33 +/- 12% (2.5 microM) and 40 +/- 8% (5 microM) (P < 0.01). The PKC-zeta inhibitor significantly attenuated PMN infiltration into the myocardium by 46-48 +/- 4% (P < 0.01) at 2.5 and 5 microM, respectively. In conclusion, these results suggest that the PKC-zeta peptide inhibitor attenuates PMN-induced post-I/R cardiac contractile dysfunction by increasing endothelial NO release and by inhibiting superoxide release from PMNs thereby attenuating PMN infiltration into I/R myocardium.
Phillipson
Aisha
A
Department of Pathology, Microbiology, and Immunology, Philadelphia College of Osteopathic Medicine, 4170 City Ave., Philadelphia, PA 19131-1694, USA.
Peterman
Ellen E
EE
Taormina
Philip
P
Harvey
Margaret
M
Brue
Richard J
RJ
Atkinson
Norrell
N
Omiyi
Didi
D
Chukwu
Uchenna
U
Young
Lindon H
LH
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology*; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011312:Pressure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000037:antagonists & inhibitors; D016277:Ventricular Function, Left; D000099221:Protein Kinase C zeta
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D011493:Protein Kinase C; D013481:Superoxides; D000099221:Protein Kinase C zeta