Abstract-Reperfusion injury after coronary occlusion is in part mediated by leukocyte activation and adhesion. Platelets may interact with polymorphonuclear granulocytes (PMNs), causing aggravated reperfusion injury. We studied whether c7E3Fab, a chimeric Fab fragment blocking platelet glycoprotein (GP) IIb/IIIa, decreases PMN-platelet-dependent myocardial dysfunction after ischemia. Isolated guinea pig hearts (nϭ5 per group) perfused at a constant flow of 5 mL/min were subjected to ischemia (15 minutes, 37°C) and reperfusion. Human PMNs (10ϫ10 6 cells, 3 mL), platelets (400ϫ10 6 , 3 mL), and fibrinogen (1 mg/mL) were infused for 3 minutes after 2 minutes of reperfusion, with or without c7E3Fab. Flow cytometry detected GPIIb/IIIa (platelets) and MAC-1 (aM2, PMNs) as well as coaggregates of both in the effluent, whereas double-fluorescence microscopy visualized intracoronary PMN-platelet coaggregates. Postischemic recovery of pressure-volume work (12-cm H 2 O preload and 60 -mm Hg afterload) was defined as the ratio of postischemic to preischemic external heart work (meanϮSEM). c7E3Fab reduced platelet GPIIb/IIIa detection to 10% of controls, blocked a transcoronary MAC-1 increase (ϩ25% without versus Ϫ23% with c7E3Fab), and inhibited PMN-platelet coaggregation in the effluent (49Ϯ12% without versus 17Ϯ2% with c7E3Fab) as well as in the hearts themselves (5.0Ϯ0.7/cm 2 without versus 1.2Ϯ0.3/cm 2 surface area with c7E3Fab). Postischemic recovery of external heart work (83Ϯ5% in cell-free hearts) declined to 46Ϯ4% after postischemic PMN-platelet infusion, but not in the presence of c7E3Fab (74Ϯ11%) or LPM19c (71Ϯ6%). We conclude that c7E3Fab inhibits formation of PMN-platelet aggregates during myocardial reperfusion, an effect that protects against PMN-platelet-dependent stunning. Key Words: abciximab Ⅲ polymorphonuclear neutrophils Ⅲ platelets Ⅲ myocardial stunning Ⅲ microcirculation Ⅲ fibrinogen P harmacological and interventional strategies aimed at reperfusion of an occluded coronary artery are standard therapeutic regimens, although a certain percentage of treatments remain unsuccessful. Aimed at reducing this margin, inhibitors of the platelet fibrinogen receptor protein, glycoprotein (GP) IIb/IIIa (␣2b/3, CD41/CD61), have been introduced, eg, a Fab fragment of the chimeric monoclonal antibody 7E3 (c7E3Fab, Abciximab [Centocor]) against human GPIIb/IIIa. 1-3 Besides improving coronary flow reserve, c7E3Fab protects from myocardial stunning in humans, which is expressed as regional wall shortening of the reperfused myocardium. 4 Factors beyond inhibition of platelet aggregation might contribute to the improvement in flow and myocardial function, eg, inhibition of platelet-endothelium or platelet-leukocyte interactions. Fibrinogen competition studies with monoclonal antibodies suggest that MAC-1 (␣M2, CD11b/CD18) is a major, if not unique, fibrinogen receptor on the polymorphonuclear neutrophil (PMN) surface. 5,6 Interestingly, MAC-1 expression decreases after application of c7E3Fab in patients undergoing pe...
Myocardial reperfusion injury is partially mediated by postis
The role of plasmalogen phospholipids for copper-induced lipid oxidation was evaluated. Using 1H-NMR we observed that the copper (CuSO4)-promoted oxidative degradation of polyunsaturated fatty acids in micellar solution was dose-dependently attenuated by the plasmalogen lysoplasmenylethanolamine from bovine brain (lysoBP-PtdEtn). This was due to a direct interaction of copper ions with the plasmalogen-specific enol ether double bond. The enol ether methine 1H signal decreased on the addition of copper, saturation being reached at a molar ratio of lysoBP-PtdEtn to copper of 1:1. The original 1H signal was recovered almost completely after the addition of EDTA. Enrichment of micelles and low-density lipoproteins (LDLs) with plasmalogen phospholipids led to a decrease in the Cu(II) concentration in the aqueous media. After loading of LDLs in vitro with BP-PtdEtn, the LDL-dependent formation of Cu(I) was decreased, in particular in particles experimentally supplemented with alpha-tocopherol. The suppression of copper-promoted lipid oxidation that was observed in the presence of plasmalogen phospholipids plus alpha-tocopherol was greater than the sum of the protective effects elicited by the two substances alone. In conclusion, the formation of a complex between copper ions and the plasmalogens accounts partly for their inhibition of copper-induced lipid oxidation.
The role of plasmalogen phospholipids for copper-induced lipid oxidation was evaluated. Using 1H-NMR we observed that the copper (CuSO4)-promoted oxidative degradation of polyunsaturated fatty acids in micellar solution was dose-dependently attenuated by the plasmalogen lysoplasmenylethanolamine from bovine brain (lysoBP-PtdEtn). This was due to a direct interaction of copper ions with the plasmalogen-specific enol ether double bond. The enol ether methine 1H signal decreased on the addition of copper, saturation being reached at a molar ratio of lysoBP-PtdEtn to copper of 1:1. The original 1H signal was recovered almost completely after the addition of EDTA. Enrichment of micelles and low-density lipoproteins (LDLs) with plasmalogen phospholipids led to a decrease in the Cu(II) concentration in the aqueous media. After loading of LDLs in vitro with BP-PtdEtn, the LDL-dependent formation of Cu(I) was decreased, in particular in particles experimentally supplemented with alpha-tocopherol. The suppression of copper-promoted lipid oxidation that was observed in the presence of plasmalogen phospholipids plus alpha-tocopherol was greater than the sum of the protective effects elicited by the two substances alone. In conclusion, the formation of a complex between copper ions and the plasmalogens accounts partly for their inhibition of copper-induced lipid oxidation.
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