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 mellitus. Diabetic (db/db) mice and their littermate nondiabetic controls were subjected to 30 min of left anterior descending coronary artery occlusion and 2 h of reperfusion. Diabetic and nondiabetic mice experienced similar-sized areas at risk per left ventricle: 50.4 +/- 2.0 and 53.4 +/- 4.1%, respectively. However, myocardial necrosis (percentage of area at risk) was significantly 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 the nondiabetic hearts. Coronary endothelial expression of P-selectin was determined using radiolabeled monoclonal antibodies (MAbs). MI-R elicited a more intense (P < 0.05) upregulation of P-selectin in the ischemic zone of diabetic than of nondiabetic myocardium: 0.310 +/- 0.034 and 0. 161 +/- 0.042 microgram MAb/g tissue. Immunoneutralization of P-selectin (RB40.34) reduced PMN accumulation in the diabetic myocardium but failed to reduce the extent of myocardial necrosis. Conversely, administration of an MAb directed against 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. Furthermore, the mechanism of this injury may not be critically dependent on P-selectin in diabetic hearts.
Jones
S P
SP
Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, Shreveport, Louisiana 71130, USA.
Girod
W G
WG
Granger
D N
DN
Palazzo
A J
AJ
Lefer
D J
DJ
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006439:Hemodynamics; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D019007:P-Selectin / Q000378:metabolism*; D010976:Platelet Count
D001786:Blood Glucose; D019007:P-Selectin; D002784:Cholesterol