Coronary and aortic endothelial function affected by feedback between adiponectin and tumor necrosis factor alpha

Objective—To verify that adiponectin and tumor necrosis factor (TNF)- reciprocally regulate their expression, thereby synergistically affecting both coronary and aortic endothelial dysfunction in type 2 diabetic mice. Methods and Results—We examined endothelium-dependent and endothelium-independent vasodilation/vasorelaxation of coronary arterioles and aortas in control mice, diabetic mice (Leprdb), and Leprdb treated with adiponectin or neutralizing antibody to TNF- (anti–TNF-). Endothelium-dependent vasodilation to acetylcholine in both coronary arterioles and aortas was blunted in Leprdb compared with control mice. Endothelium-independent vasodilation to sodium nitroprusside was comparable. Adiponectin and anti–TNF- improved acetylcholine-induced vasodilation of coronary arterioles and aortas in Leprdb without affecting dilator response to sodium nitroprusside. Adiponectin protein expression was significantly reduced, and TNF- protein expression was significantly greater, in coronary arterioles and aortas of Leprdb compared with control mice. Immunofluorescence staining results indicate that adiponectin was colocalized with endothelial cells. Anti–TNF- treatment upregulated adiponectin protein expression in Leprdb coronary arterioles and aortas. Adiponectin administration reduced TNF- protein expression in Leprdb. Although adiponectin receptor 1 protein expression in coronary arterioles and aortas was similar between control and diabetic mice, adiponectin receptor 2 protein expression was significantly reduced in Leprdb. Both adiponectin and anti–TNF- inhibited IB phosphorylation and nuclear factor B protein expression in Leprdb, suggesting that adiponectin an