Neutrophil (PMN) adhesion to the vascular endothelium is an important mechanism of myocardial reperfusion injury. The adhesion process is initially mediated by selectins (e.g., P- and L-selectin), and monoclonal antibodies directed against these adhesion molecules exert cardioprotective activity in ischemia/reperfusion models. The counterreceptors for these selectins are thought to be carbohydrate-containing moieties. In this connection, we studied the effect of a soluble sialyl Lewisx-containing oligosaccharide (SLex-OS) on PMN-endothelial interactions in a feline model of myocardial ischemia/reperfusion (MI/R). SLex-OS (10 mg/kg), administered 10 min before R, significantly reduced myocardial necrosis compared with its vehicle 270 min after reperfusion (6 +/- 1% vs. 35 +/- 4% of area at risk, P < 0.01). The cardioprotection was confirmed by significantly lower plasma creatine kinase activities in SLex-OS vs. vehicle-treated cats (P < 0.01). Cardiac contractility (dP/dt max) of cats receiving SLex-OS was significantly preserved after 270 min of R (97 +/- 2% vs. 78 +/- 5% of initial, P < 0.01). Furthermore, endothelium-dependent relaxation to acetylcholine in coronary artery rings isolated from MI/R cats treated with SLex-OS was significantly preserved (73 +/- 7% vs. 22 +/- 6% vasorelaxation, P < 0.01). In vitro PMN adherence to coronary vascular endothelium after 270 min of R was significantly attenuated in the SLex-OS-treated group compared with the vehicle group (14 +/- 5 vs. 91 +/- 12 PMN/mm2, P < 0.01). Our results indicate that a SLex-OS is cardioprotective and preserves coronary endothelial function after MI/R, indicating an important role of sialyl Lewisx in PMN accumulation, endothelial dysfunction, and myocardial injury in myocardial ischemia/reperfusion.
M Buerke, A S Weyrich, Z Zheng, F C Gaeta, M J Forrest, A M Lefer