A novel strategy for myocardial protection by combined antibody therapy inhibiting both P-selectin and intercellular adhesion molecule-1 via retrograde intracoronary route.
BACKGROUND
Antibody therapy to inhibit either P-selectin or intercellular adhesion molecule-1 (ICAM-1) has been reported to provide myocardial protection against leukocyte-mediated reperfusion injury. Because these molecules play different roles in the leukocyte-endothelial interaction, co-inhibition of both may achieve further enhanced cardioprotection. In addition, the therapeutic efficacy of such antibody therapy may be affected by the delivery route used. Retrograde intracoronary infusion will offer an effective, direct access to the postcapillary venules, where the target event (leukocyte-endothelial interaction) takes place. We investigated the feasibility and efficiency of the combined antibody therapy targeting both P-selection and ICAM-1 via the retrograde intracoronary route to attenuate myocardial ischemia-reperfusion injury.


RESULTS
Lewis rats underwent 30-minute left coronary artery occlusion. Just before reperfusion, anti-P-selectin monoclonal antibody (150 microg/kg), anti-ICAM-1 monoclonal antibody (200 microg/kg), both antibodies together, or control antibody were retrogradely infused into the left cardiac vein. At 24 hours after reperfusion, administration of either anti-P-selectin or anti-ICAM-1 antibody significantly (P<0.05) improved left ventricular ejection fraction and attenuated infarct size (40.6+/-3.2% and 34.8+/-3.5%, respectively) compared with the control (56.8+/-3.4%). This was associated with reduced leukocyte accumulation and improved regional blood flow in the ischemic area. Noticeably, co-administration of both antibodies achieved a much greater reduction in infarct size (19.1+/-3.6%), associated with greater attenuation in leukocyte infiltration, compared with administration of either single antibody.


CONCLUSIONS
Combined antibody therapy inhibiting both P-selectin and ICAM-1 via the retrograde intracoronary route could be a promising new strategy for myocardial protection against ischemia-reperfusion injury.
Fukushima
Satsuki
S
Harefield Heart Science Centre, National Heart & Lung Institute, Faculty of Medicine, Imperial College London, UK.
Coppen
Steven R
SR
Varela-Carver
Anabel
A
Yamahara
Kenichi
K
Sarathchandra
Padmini
P
Smolenski
Ryszard T
RT
Yacoub
Magdi H
MH
Suzuki
Ken
K
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003326:Coronary Circulation; D003331:Coronary Vessels; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology; D005240:Feasibility Studies; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D007275:Injections, Intravenous / Q000379:methods; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009205:Myocarditis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D009929:Organ Size; D019007:P-Selectin / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D013318:Stroke Volume; D014463:Ultrasonography
D000911:Antibodies, Monoclonal; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1