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1 Pathology, Microbiology and Immunology, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: LindonYo{at}PCOM.edu.
Ischemia followed by reperfusion (I/R) in the presence of polymorphonuclear leukocytes (PMNs) results in a marked cardiac contractile dysfunction. A cell permeable Protein kinase C (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 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 µM, n=6) significantly attenuated PMN-induced cardiac dysfunction compared to 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 indices (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 µM, P<0.05) and 54±5% (5 µM, P<0.01) over basal values from rat aorta, and significantly inhibited superoxide release from phorbol-12-myristate-13-acetate stimulated rat PMNs by 33±12% (2.5 µM) and 40±8% (5 µM) (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 µM 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.
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