Blockade of platelet endothelial cell adhesion molecule-1 protects against myocardial ischemia and reperfusion injury in cats.
Polymorphonuclear leukocytes have been shown to play an important role in myocardial ischemia (MI) and reperfusion (R) injury. Since blockade of platelet-endothelial cell adhesion molecules (PECAM-1) inhibits neutrophil transmigration in vitro and in vivo, the effects of a polygonal Ab directed against PECAM-1 were examined in a feline model of Ml/R. We established cross-reactivity of our anti-human PECAM-1 Ab to cat coronary vasculature and neutrophils by immunohistochemistry and flow cytometry. The anti-PECAM-1 Ab markedly blocked leukocyte transmigration into the peritoneal cavity of cats after glycogen-induced peritonitis. Then, anti-PECAM-1 Ab (1 mg/kg) was tested to determine whether it attenuates MI/R injury in a well characterized feline model of Ml and R. Anti-PECAM-1 Ab administered 10 min before R significantly inhibited the myocardial necrosis seen 4.5 h post-R compared with that in MI/R cats treated with control isotype rabbit IgG (12 +/- 2 vs 29 +/- 4% of area at risk; p less than 0.01) and significantly attenuated the rise in plasma creatine kinase activity (p less than 0.05). The Ab did not prevent increases in cardiac myeloperoxidase activity within the affected regions and did not significantly inhibit autologous neutrophil adhesion to coronary endothelium after stimulation of either neutrophils (by leukotriene B4) or coronary endothelium (by thrombin) in vitro. These results indicate that in vivo blockade of PECAM-1 significantly attenuates MI/R injury, presumably by inhibiting transendothelial migration of neutrophils.
Murohara
T
T
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Delyani
J A
JA
Albelda
S M
SM
Lefer
A M
AM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015214:Antigens, Differentiation, Myelomonocytic / Q000737:chemistry / Q000276:immunology*; D001666:Binding Sites, Antibody; D001667:Binding, Competitive / Q000276:immunology; D002415:Cats; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D003402:Creatine Kinase / Q000097:blood; D004562:Electrocardiography; D004730:Endothelium, Vascular / Q000276:immunology; D005434:Flow Cytometry; D006439:Hemodynamics / Q000276:immunology; D007150:Immunohistochemistry; D017202:Myocardial Ischemia / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D009336:Necrosis; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013481:Superoxides / Q000097:blood
D000911:Antibodies, Monoclonal; D015214:Antigens, Differentiation, Myelomonocytic; D015815:Cell Adhesion Molecules; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013481:Superoxides; D003402:Creatine Kinase