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TRANSLATIONAL PHYSIOLOGY

Role of MCP-1 in tumor necrosis factor--induced endothelial dysfunction in type 2 diabetic mice

¹Michael E. DeBakey Institute and Department of ²Veterinary Integrative Biosciences Texas A&M University, College Station, Texas and Department of ³Systems Biology and Translational Medicine, Texas A&M University, College Station, Texas; and ⁴Departments of Internal Medicine, Medical Pharmacology and Physiology and Nutritional Sciences, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri

Submitted April 28, 2009 ; accepted in final form August 3, 2009

Tumor necrosis factor- (TNF-) upregulates the expression of monocyte chemoattractant protein-1 (MCP-1) and adhesion molecules in type 2 diabetes. We hypothesized that TNF- and MCP-1 may interact to contribute to the evolution of vascular inflammation and endothelial dysfunction in coronary arterioles in type 2 diabetes. To test this hypothesis, we administered anti-MCP-1 to block MCP-1 signaling in genetically modified mice with type 2 diabetes (Lepr^db) and in heterozygote (m Lepr^db) lean control. Anti-MCP-1 partially restored vasodilation to the endothelium-dependent vasodilator acetylcholine in isolated, cannulated, and pressurized coronary arterioles in Lepr^db mice but did not affect vasodilation in m Lepr^db mice. Anti-MCP-1 attenuated superoxide production and the protein expression of nitrotyrosine, which is an indicator of peroxynitrite production, in isolated coronary arterioles of Lepr^db mice. Immunostaining results showed that the expression of MCP-1 and vascular cellular adhesion molecule-1 is colocalized with endothelial cells and macrophages. Anti-TNF- or anti-MCP-1 markedly reduced macrophage infiltration and the number of MCP-1-positive endothelium in Lepr^db mice. The neutralization of TNF- or anti-MCP-1 reduced the expression of adhesion molecules, suggesting that proinflammatory cytokines interact to amplify the signaling process that leads to vascular dysfunction. These findings demonstrate that the endothelial dysfunction occurring in type 2 diabetes is the result of the effects of the inflammatory cytokine TNF- and TNF--related signaling, including the expression of MCP-1 and adhesion molecules, which further exacerbates vessel inflammation and oxidative stress.

coronary microcirculation; cytokines; inflammation; vasodilation