Tetrahydrobiopterin (BH4) attenuates neutrophil adhesion/transmigration in myocardial ischemia/reperfusion injury

Abstract

Attenuating endothelial dysfunction during early reperfusion (i.e., within the first 5 min) inhibits upregulation of endothelial adhesion molecules, attenuates PMN-endothelium interaction, and restores post-reperfusion cardiac contractile function. BH4 is an essential cofactor of endothelial nitric oxide synthase to produce nitric oxide. We hypothesize that BH4, not dihydrobiopterin (BH2, i.e., oxidized BH4), given during reperfusion will attenuate PMN vascular adherence and infiltration and restore cardiac function in isolated rat hearts subjected to ischemia (20 min) and reperfusion (45 min)and reperfused with PMNs. In BH4 treated I/R+PMN hearts (10uM, n=6), left ventricular developed pressure (LVDP) at 45 min post reperfusion significantly recovered to 85±8% of baseline, whereas I/R+PMN hearts and BH2-perfused hearts only recovered to 53±7% and 64±9% of baseline (P<0.01). IR/PMN perfused BH4 hearts were associated with decreased PMN coronary vascular adherence, tissue infiltration, and attenuated ICAM-1 expression, compared to IR/PMN hearts or BH2-perfused hearts. This preliminary data suggest that BH4 attenuates PMN induced post-I/R LVDP dysfunction, in part, by attenuating PMN vascular adherence and tissue infiltration, possibly by inhibiting ICAM-1 expression. This study was supported by NHLBI Grant 1R15HL-76235-01 and Center For Chronic Disorders Of Aging. Philadelphia College of Osteopathic Medicine.