Complement inhibition reduces injury in the type 2 diabetic heart following ischemia and reperfusion.
Chronic inflammation exacerbates the cardiovascular complications of diabetes. Complement activation plays an important role in the inflammatory response and is known to be involved in ischemia-reperfusion (I/R) injury in the nondiabetic heart. The purpose of this study was to determine if increased complement deposition explains, in part, the increased severity of neutrophil-mediated I/R injury in the type 2 diabetic heart. Nondiabetic Zucker lean control (ZLC) and Zucker diabetic fatty (ZDF) rats underwent 30 min of coronary artery occlusion followed by 120 min of reperfusion. Another group of ZDF rats was treated with the complement inhibitor FUT-175 before reperfusion. Left ventricular (LV) tissue samples were stained for complement deposition and neutrophil accumulation following reperfusion. We found significantly more complement deposition in the ZDF LV compared with the ZLC (P < 0.05), and complement deposition was associated with significantly greater neutrophil accumulation. In whole blood samples taken preischemia and at 120 min reperfusion, neutrophils exhibited significantly more CD11b expression in the ZDF group compared with the ZLC group (P < 0.05). Furthermore, intracellular adhesion molecule (ICAM)-1 expression following I/R was increased significantly in ZDF hearts compared with ZLC hearts (P < 0.001). These results indicate that, in the ZDF heart, increased ICAM-1 and polymorphonuclear neutrophil (PMN) CD11b expression play a role in increasing PMN accumulation following I/R. The infarct size of the ZDF was significantly greater than ZLC (P < 0.05), and treatment with FUT-175 significantly decreased infarct size, complement deposition, and PMN accumulation in the diabetic heart. These findings indicate an exacerbated inflammatory response in the type 2 diabetic heart that contributes to the increased tissue injury observed following ischemia and reperfusion.
La Bonte
Laura R
LR
Physiological Sciences Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ 85724-5071, USA. labonte@email.arizona.edu
Davis-Gorman
Grace
G
Stahl
Gregory L
GL
McDonagh
Paul F
PF
D000818:Animals; D001550:Benzamidines; D001772:Blood Cell Count; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D039481:CD11b Antigen / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D016923:Cell Death / Q000502:physiology; D003167:Complement Activation / Q000187:drug effects / Q000502:physiology; D003176:Complement C3 / Q000378:metabolism; D051056:Complement Inactivating Agents / Q000627:therapeutic use*; D003165:Complement System Proteins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology*; D003925:Diabetic Angiopathies / Q000473:pathology / Q000517:prevention & control*; D005434:Flow Cytometry; D006146:Guanidines / Q000494:pharmacology; D006339:Heart Rate / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker
D001550:Benzamidines; D001786:Blood Glucose; D039481:CD11b Antigen; D015815:Cell Adhesion Molecules; D003176:Complement C3; D051056:Complement Inactivating Agents; D006146:Guanidines; D018799:Intercellular Adhesion Molecule-1; D003165:Complement System Proteins; C032855:nafamostat