Reperfusion injury is not affected by blockade of P-selectin in the diabetic mouse heart

We examined the mechanisms responsible for myocardial ischemia-reperfusion (MI-R) injury in a well-characterized animal model of type II diabetes mell itus. Diabetic (db/db) mice and their littermate nondiabetic controls were subjected to 30 min of left anterior descending coronary artery occlusion a nd 2 h of reperfusion. Diabetic and nondiabetic mice experienced similar-si zed areas at risk per left ventricle: 50.4 +/- 2.0 and 53.4 +/- 4.1%, respe ctively. However, myocardial necrosis (percentage of area at risk) was sign ificantly greater (P < 0.001) in diabetic than in nondiabetic animals: 56.3 +/- 2.8 and 27.2 +/- 3.1%, respectively. Histological examination revealed significantly (P < 0.05) more neutrophils (PMNs) in the diabetic than in t he nondiabetic hearts. Coronary endothelial expression of P-selectin was de termined using radiolabeled monoclonal antibodies (MAbs). MI-R elicited a m ore intense (P < 0.05) upregulation of P-selectin in the ischemic zone of d iabetic than of nondiabetic myocardium: 0.310 +/- 0.034 and 0.161 +/- 0.942 mu g MAb/g tissue. Immunoneutralization of P-selectin (RB40.34) reduced PM N accumulation in the diabetic myocardium but failed to reduce the extent o f myocardial necrosis. Conversely, administration of an MAb directed agains t CD18 (GAME46) reduced PMN infiltration and attenuated the infarct size in the diabetic hearts. These results suggest that the diabetic heart is more susceptible to ischemia-reperfusion injury than normal myocardium. Further more, the mechanism of this injury may not be critically dependent on P-sel ectin in diabetic hearts.