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CARDIOVASCULAR

Protein Kinase C II Peptide Inhibitor Exerts Cardioprotective Effects in Rat Cardiac Ischemia/Reperfusion Injury

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

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) II peptide inhibitor was used to test the hypothesis that PKC II inhibition could attenuate PMN-induced cardiac dysfunction by suppression of superoxide production from PMNs and increase NO release from vascular endothelium. The effects of the PKC II peptide inhibitor were examined in isolated ischemic (20 min) and reperfused (45 min) rat hearts with PMNs. The PKC II inhibitor (10 µM; n = 7) significantly attenuated PMN-induced cardiac dysfunction compared with I/R hearts (n = 9) receiving PMNs alone in left ventricular developed pressure (LVDP) and the maximal rate of LVDP (+dP/dt_max) cardiac function indices (p < 0.01). The PKC II inhibitor at 10 µM significantly increased endothelial NO release from a basal value of 1.85 ± 0.18 pmol NO/mg tissue to 3.49 ± 0.62 pmol NO/mg tissue from rat aorta. It also significantly inhibited superoxide release (i.e., absorbance) from N-formyl-L-methionyl-L-leucyl-L-phenylalanine-stimulated rat PMNs from 0.13 ± 0.01 to 0.02 ± 0.004 (p < 0.01) at 10 µM. Histological analysis of the left ventricle of representative rat hearts from each group showed that the PKC II peptide inhibitor-treated hearts experienced a marked reduction in PMN vascular adherence and infiltration into the postreperfused cardiac tissue compared with I/R + PMN hearts (p < 0.01). These results suggest that the PKC II peptide inhibitor attenuates PMN-induced post-I/R cardiac contractile dysfunction by increasing endothelial NO release and by inhibiting superoxide release from PMNs.

Address correspondence to: Dr. Lindon H. Young, Department of Pathology, Microbiology, and Immunology, Philadelphia College of Osteopathic Medicine, 4170 City Ave., Philadelphia, PA 19131. E-mail: lindonyo{at}pcom.edu

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