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.
Ma
X L
XL
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Lefer
D J
DJ
Lefer
A M
AM
Rothlein
R
R
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