title: Toll-like receptor 4 mutation protects obese mice against endothelial dysfunction by decreasing NADPH oxidase isoforms 1 and 4.
abstract: OBJECTIVE
  To analyze the role of toll-like receptor 4 in modulating metabolism and endothelial function.
  
  
  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(db/db) 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(db/db) 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.
authors: Department of Pharmacology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Chao-Fan
authors: CF
authors: Liang
authors: Jacky Tc
authors: JT
authors: Liu
authors: Yu
authors: Y
authors: Wang
authors: Aimin
authors: A
authors: Xu
authors: Paul M
authors: PM
authors: Vanhoutte
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000503:physiopathology; D002339:Carotid Arteries / Q000201:enzymology / Q000503:physiopathology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D008638:Mesenteric Arteries / Q000201:enzymology / Q000503:physiopathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology; D009154:Mutation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D018384:Oxidative Stress; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D054411:Receptors, Leptin; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014665:Vasodilator Agents; C515447:leptin receptor, mouse; D013481:Superoxides; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C422943:Nox4 protein, mouse