title: Altered MAPK signaling in progressive deterioration of endothelial function in diabetic mice.
abstract: We aimed to investigate specific roles of mitogen-activated protein kinases (MAPK) in the deterioration of endothelial function during the progression of diabetes and the potential therapeutic effects of MAPK inhibitors and agonists in the amelioration of endothelial function. Protein expression and phosphorylation of p38, c-Jun NH(2)-terminal kinase (JNK), and extracellular signal-regulated kinase (Erk) were assessed in mesenteric arteries of 3- (3M) and 9-month-old (9M) male diabetic and control mice. The expression of p38, JNK, and Erk was comparable in all groups of mice, but the phosphorylation of p38 and JNK was increased in 3M and further increased in 9M diabetic mice, whereas the phosphorylation of Erk was substantially reduced in 9M diabetic mice. NADPH oxidase-dependent superoxide production was significantly increased in vessels of two ages of diabetic mice. Inhibition of either p38 with SB203580 or JNK with SP600125 reduced superoxide production and improved shear stress-induced dilation (SSID) in 3M, but not in 9M, diabetic mice. Treating the vessels of 9M diabetic mice with resveratrol increased Erk phosphorylation and shear stress-induced endothelial nitric oxide synthase (eNOS) phosphorylation and activity, but resveratrol alone did not improve SSID. Administration of resveratrol and SB203580 or resveratrol and SP600125 together significantly improved SSID in vessels of 9M diabetic mice. The improved response was prevented by U0126, an Erk inhibitor. Thus, p38/JNK-dependent increase in oxidative stress diminished nitric oxide-mediated dilation in vessels of 3M diabetic mice. Oxidative stress and impaired Erk-dependent activation of eNOS exacerbates endothelial dysfunction in the advanced stage of diabetes.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York, USA. an_huang@nymc.edu
authors.forename: An
authors.initials: A
authors.lastname: Huang
authors.forename: Yang-Ming
authors.initials: YM
authors.lastname: Yang
authors.forename: Changdong
authors.initials: C
authors.lastname: Yan
authors.forename: Gabor
authors.initials: G
authors.lastname: Kaley
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000627:therapeutic use; D002070:Butadienes / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007093:Imidazoles / Q000627:therapeutic use; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009570:Nitriles / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011725:Pyridines / Q000627:therapeutic use; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000627:therapeutic use; D013481:Superoxides / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000873:Anthracenes; D002070:Butadienes; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; D054411:Receptors, Leptin; D013267:Stilbenes; C113580:U 0126; C515447:leptin receptor, mouse; D013481:Superoxides; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D000077185:Resveratrol