Blockade of cell adhesion by a small molecule selectin antagonist attenuates myocardial ischemia/reperfusion injury.
Reperfusion injury is related closely to inflammatory reactions such as the activation and accumulation of neutrophils. We investigated the efficacy of a novel small molecule selectin antagonist (bimosiamose) in a rat model of transient left coronary artery occlusion (30 min) and reperfusion (24 h). Treatment with bimosiamose (25 mg/kg, intravenously at reperfusion) showed a significant reduction in infarction area/area at risk of approximately 41% compared to vehicle control (P=0.01) and preserved the left ventricular function. The accumulation of polymorphonuclear neutrophils at the site of area at risk was decreased significantly, accompanied by 78% reduction of the myeloperoxidase activity. Parallel-plate flow chamber analysis revealed that bimosiamose showed a significant inhibition in rolling (62%, P<0.001) and adhesion (38%, P<0.05) of HL-60 cells to activated human umbilical vein endothelial cells compared with vehicle control. This study demonstrates for the first time that bimosiamose, a novel small molecule selectin antagonist, attenuates significantly ischemia/reperfusion injury.
Onai
Yasuyuki
Y
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan.
Suzuki
Jun-ichi
J
Nishiwaki
Yasunobu
Y
Gotoh
Ryo
R
Berens
Kurt
K
Dixon
Richard
R
Yoshida
Masayuki
M
Ito
Hiroshi
H
Isobe
Mitsuaki
M
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use*; D002478:Cells, Cultured; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D008358:Mannose / Q000031:analogs & derivatives; D008362:Mannosides / Q000494:pharmacology* / Q000627:therapeutic use*; D017202:Myocardial Ischemia / Q000473:pathology* / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019087:Selectins / Q000502:physiology*
D001713:Biphenyl Compounds; D008362:Mannosides; D019087:Selectins; C108700:bimosiamose disodium; D008358:Mannose