Toll-Like Receptor 4 Mutation Protects Obese Mice Against Endothelial Dysfunction by Decreasing NADPH Oxidase Isoforms 1 and 4

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 33; no. 4; pp. 777 - 784
• Main Authors: Liang, Chao-Fan, Liu, Jacky TC, Wang, Yu, Xu, Aimin, Vanhoutte, Paul M
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01-04-2013
• Subjects: 6-Ketoprostaglandin F1 alpha - metabolism; Animals; Aorta - enzymology; Aorta - physiopathology; Carotid Arteries - enzymology; Carotid Arteries - physiopathology; Cyclooxygenase 1 - metabolism; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - physiopathology; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Lipopolysaccharides - pharmacology; Membrane Proteins - metabolism; Mesenteric Arteries - enzymology; Mesenteric Arteries - physiopathology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - physiopathology; Mutation; NADH, NADPH Oxidoreductases - antagonists & inhibitors; NADH, NADPH Oxidoreductases - genetics; NADH, NADPH Oxidoreductases - metabolism; NADPH Oxidase 1; NADPH Oxidase 4; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Obesity - enzymology; Obesity - genetics; Obesity - physiopathology; Oxidative Stress; Phosphorylation; Receptors, Leptin - deficiency; Receptors, Leptin - genetics; RNA, Messenger - metabolism; Superoxides - metabolism; Toll-Like Receptor 4 - deficiency; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Vasoconstriction - drug effects; Vasodilation - drug effects; Vasodilator Agents - pharmacology
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.112.301087

OBJECTIVE—To analyze the role of toll-like receptor 4 in modulating metabolism and endothelial function.
APPROACH AND RESULTS—Type 2 diabetic mice with mutated toll-like receptor 4 (DWM) were protected from hyperglycemia and hypertension, despite an increased body weight. Isometric tension was measured in arterial rings with endothelium. Relaxations to acetylcholine were blunted in aortae and mesenteric arteries of Lepr mice, but not in DWM mice; the endothelial NO synthase dimer/monomer ratio and endothelial NO synthase phosphorylation levels were higher in DWM preparations. These differences were abolished by apocynin. Contractions to acetylcholine (in the presence of L-NAME) were larger in carotid arteries from Lepr mice than from DWM mice and were inhibited by indomethacin and SC560, demonstrating involvement of cyclooxygenase-1. The release of 6-ketoprostaglandin F1α was lower in DWM mice arteries, implying lower cyclooxygenase-1 activity. Apocynin, manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin, catalase, and diethyldithiocarbamate inhibited endothelium-dependent contractions. The mRNA and protein levels of NADPH oxidase isoforms NOX1 and NOX4 were downregulated in DWM mice arteries. The in vivo and in vitro administration of lipopolysaccharide caused endothelial dysfunction in the arteries of wild-type, but not toll-like receptor 4–mutated mice.
CONCLUSIONS—Toll-like receptor 4 plays a key role in obesity and diabetes-associated endothelial dysfunction by increasing oxidative stress.