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


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 less than 0.01), lower myeloperoxidase activity in ischemic myocardial tissue (0.2 +/- 0.03 units/100 mg ischemic tissue, p less than 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.
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
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Lefer
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Lefer
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Rothlein
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D002415:Cats; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000276:immunology*; D003326:Coronary Circulation; D003327:Coronary Disease / Q000503:physiopathology*; D004594:Electrophysiology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics; D018799:Intercellular Adhesion Molecule-1; D008297:Male; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D009504:Neutrophils / Q000473:pathology / Q000502:physiology
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D018799:Intercellular Adhesion Molecule-1