Cardioprotective Effects of a Novel Proteasome Inhibitor Following Ischemia and Reperfusion in the Isolated Perfused Rat Heart

Abstract

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as myocardial injury. These effects are due in large part to endothelial dysfunction leading to an upregulation of cell adhesion molecules and subsequent neutrophil induced cardiac injury. The proteasome inhibitor, PS-519, has been shown to attenuate leukocyte-endothelial cell interactions. We tested the effects of PS-519 on neutrophil mediated cardiac dysfunction in ischemia/reperfusion. This study examines the effects of PS-519 in a neutrophil dependent isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min). Administration of PS-519 (0.01, 0.1, 0.3, 1.0 mg/kg) to I/R hearts perfused with PMNs improved coronary flow, and preserved left ventricular developed pressure (LVDP) and +dP/dtmax as indices of cardiac contractile function. At 1.0 mg/kg, PS-519 treated hearts exhibited a final LVDP of 98±3% of initial compared to 52±8% in I/R hearts receiving only vehicle (P<0.001). In addition, PS-519 significantly reduced PMN accumulation in the ischemic myocardium from 25.1±2.1 PMNs/mm2in untreated hearts to 7.3 PMNs/mm2, and attenuated P-selectin surface expression on coronary vascular endothelium from 7.1±0.3% to 1.4±0.2% (P<0.01). These results provide evidence that PS-519 is a potent and effective cardioprotective agent that inhibits P-selectin leukocyte-endothelial cell interactions and preserves cardiac contractile function and coronary perfusion following myocardial ischemia and reperfusion.