The combination of protein kinase C epsilon activator (PKC ε +) and tetrahydrobiopterin (BH4) exerts cardioprotective effects in ischemia/reperfusion injury (I/R) when given during reperfusion

Abstract

In the presence of polymorphonuclear leukocytes (PMNs) during reperfusion, following myocardial ischemia, cardiac contractile dysfunction is observed. Isolated ischemic (20 min) and reperfused (45 min) rat hearts in the presence of activated PMNs were studied. A cell permeable peptide (PKC ε+) that enhances interaction of PKC ε with endothelial nitric oxide synthase (eNOS) to increase nitric oxide (NO) release, and BH4, an essential cofactor of eNOS, were given during the first five min of reperfusion. In hearts given PKC ε+ (10 μM) and BH4 (5 μM) (n=7) with PMNs, left ventricular developed pressure (LVDP) significantly recovered to 92% ± 11% of baseline values compared to I/R + PMN hearts (n=5) (48% ± 7%) (p<0.05) and the maximal rate of LVDP (+dP/dtmax) significantly recovered to 83% ± 7% compared to I/R + PMN hearts (34% ± 4%) (p<0.01) at 45 min reperfusion. The cardioprotective effects of PKC ε+ and BH4 were associated with an approximate 50% decrease in PMN infiltration in post‐reperfused hearts as confirmed by myeloperoxidase assay. These results suggest that the combination of PKC ε+ and BH4 attenuates PMN‐induced cardiac contractile dysfunction after I/R, in part by promotion of eNOS to increase NO release and inhibition of PMN infiltration in post‐reperfused hearts. This study was supported by NHLBI Grant 1R15HL‐76235‐01 and the Center for the Chronic Disorders of Aging at PCOM.