Protein kinase C-ζ 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/dtmax) cardiac function indexes (P < 0.01), and these cardioprotective effects were blocked by the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (50 µM). 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. [PUBLICATION ABSTRACT]