Coronary endothelial and cardiac protective effects of a monoclonal antibody to intercellular adhesion molecule-1 in myocardial ischemia and reperfusion

Abstract

Background. Intercellular adhesion molecule-1 (ICAM-1) is a major ligand on endothelial cells for adherence of activated polymorphonuclear leukocytes (PMNs). The major purpose of this study was to study the effects of RR1/1, a monoclonal antibody against ICAM-1 (i.e., MAb RR1/1), on myocardial injury and endothelial dysfunction associated with myocardial ischemia and reperfusion. Methods and Results. Either MAb RR1/1 (2 mg/kg, n=7), an antibody that was found to bind selectively to endothelial cells in the cat, or MAb R3.1 (2 mg/kg, n=7), a nonbinding control antibody, was given as an intravenous bolus 10 minutes before reperfusion. Two hundred eighty minutes later, hearts were excised. The left ventricle area-at-risk (AAR) was similar in MAb RR1/1 (29±2%) and MAb R3.1 (30±3%) groups. In MAb R3.1-treated cats, 90 minutes of myocardial ischemia plus 4.5 hours of reperfusion induced a significant myocardial injury (necrotic tissue/AAR, 28±2%), high myeloperoxidase activity (0.65±0.16 units/100 mg ischemic tissue), and a marked decrease in endothelium-dependent vasorelaxation in isolated left anterior descending coronary arteries (vasorelaxation to acetylcholine, 29±3%) with no change in endothelium-independent vasorelaxation (relaxation to NaNO2, 91±3%). However, cats treated with MAb RR1/1 developed significantly less myocardial necrosis (10±2% of the AAR, p<0.01), lower myeloperoxidase activity in ischemic myocardial tissue (0.2±0.03 units/100 mg ischemic tissue, p<0.01), and enhanced vasorelaxant responses to endothelial-dependent relaxation to acetylcholine (53±5%) compared with ischemic/reperfused cats treated with MAb R3.1. Furthermore, addition of MAb RR1/1 in vitro significantly inhibited unstimulated PMN adherence to ischemic-reperfused coronary artery endothelium. Conclusions. These results suggest that ICAM-1-dependent PMN adherence plays an important role in reperfusion injury, and that PMN adherence and infiltration contribute significantly to coronary endothelial dysfunction.