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Protein kinase C- inhibition exerts cardioprotective effects in ischemia-reperfusion injury

Department of Pathology, Microbiology, and Immunology, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania

Submitted 15 September 2003 ; accepted in final form 4 February 2005

Ischemia followed by reperfusion (I/R) in the presence of polymorphonuclear leukocytes (PMNs) results in marked cardiac contractile dysfunction. A cell-permeable PKC- peptide inhibitor was used to test the hypothesis that PKC- 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- peptide inhibitor were examined in isolated ischemic (20 min) and reperfused (45 min) rat hearts reperfused with PMNs. The PKC- inhibitor (2.5 or 5 µM, 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 µM). Furthermore, the PKC- 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 the 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- 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- 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.

neutrophils; superoxide radicals; left ventricular developed pressure; endothelial dysfunction

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