| Title | Role of MCP-1 in tumor necrosis factor-alpha-induced endothelial dysfunction in type 2 diabetic mice. | | Author(s) | Yang J, Park Y, Zhang H, Gao X, Wilson E, Zimmer W, Abbott L, Zhang C | | Institution | Michael E DeBakey Institute, Texas A&M University, College Station, Texas, USA. | | Source | Am J Physiol Heart Circ Physiol 2009 Oct; 297(4):H1208-16. | | MeSH | Animals
Arterioles
Biological Markers
Chemokine CCL2
Coronary Vessels
Diabetes Mellitus, Type 2
Diabetic Angiopathies
Disease Models, Animal
Dose-Response Relationship, Drug
Endothelium, Vascular
Female
I-kappa B Proteins
Inflammation Mediators
Macrophages
Male
Mice
Mice, Knockout
NF-kappa B
Nitric Oxide
Oxidative Stress
Peroxynitrous Acid
Phosphorylation
Receptors, Leptin
Serine
Signal Transduction
Superoxides
Tumor Necrosis Factor-alpha
Tyrosine
Vascular Cell Adhesion Molecule-1
Vasodilation
Vasodilator Agents
| | Abstract | Tumor necrosis factor-alpha (TNF-alpha) upregulates the expression of monocyte chemoattractant protein-1 (MCP-1) and adhesion molecules in type 2 diabetes. We hypothesized that TNF-alpha 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-alpha or anti-MCP-1 markedly reduced macrophage infiltration and the number of MCP-1-positive endothelium in Lepr(db) mice. The neutralization of TNF-alpha 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-alpha and TNF-alpha-related signaling, including the expression of MCP-1 and adhesion molecules, which further exacerbates vessel inflammation and oxidative stress. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
| | PubMed ID | 19666844 |
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