Coronary and Aortic Endothelial Function Affected by Feedback Between Adiponectin and Tumor Necrosis Factor α in Type 2 Diabetic Mice

Objective-To verify that adiponectin and tumor necrosis factor (TNF)-alpha 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 (Lepr(db)), and Lepr(db) treated with adiponectin or neutralizing antibody to TNF-alpha (anti-TNF-alpha). Endothelium-dependent vasodilation to acetylcholine in both coronary arterioles and aortas was blunted in Lepr(db) compared with control mice. Endothelium-independent vasodilation to sodium nitroprusside was comparable. Adiponectin and anti-TNF-alpha improved acetylcholine-induced vasodilation of coronary arterioles and aortas in Lepr(db) without affecting dilator response to sodium nitroprusside. Adiponectin protein expression was significantly reduced, and TNF-alpha protein expression was significantly greater, in coronary arterioles and aortas of Lepr(db) compared with control mice. Immunofluorescence staining results indicate that adiponectin was colocalized with endothelial cells. Anti-TNF-alpha treatment upregulated adiponectin protein expression in Lepr(db) coronary arterioles and aortas. Adiponectin administration reduced TNF-alpha protein expression in Lepr(db). 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 Lepr(db). Both adiponectin and anti-TNF-alpha inhibited I kappa B alpha phosphorylation and nuclear factor kappa B protein expression in Lepr(db), suggesting that adiponectin and TNF-alpha signaling may converge on nuclear factor kappa B to reciprocally regulate their expression. Conclusion-A reciprocal suppression occurs between adiponectin and TNF-alpha that fundamentally affects the regulation of coronary and aortic endothelial function in type 2 diabetic mice. (Arterioscler Thromb Vasc Biol. 2010; 30: 2156-2163.)