Enhanced p22phox expression impairs vascular function through p38 and ERK1/2 MAP kinase-dependent mechanisms in type 2 diabetic mice.
Type 2 diabetes is associated with vascular complication. We hypothesized that increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p22(phox) expression impairs vascular endothelium-dependent relaxation (EDR) in type 2 diabetes. Type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice were treated with reactive oxygen species (ROS) scavenger, polyethylene glycol superoxide dismutase (1,000 U/kg daily ip), or small interfering RNA p22(phox) (p22(phox)-lentivirus-small interfering RNA, 100 μg iv, 2 times/wk) for 1 mo. EDR was impaired in microvascular bed (coronary arteriole and femoral and mesenteric resistance arteries) from diabetic mice compared with control. Interestingly, ROS scavenger and p22(phox) downregulation did not affect blood glucose level or body weight but significantly improved EDR. Mitogen-activated protein kinases (ERK1/2 and p38) phosphorylation and NADPH oxidase activity were increased in arteries from diabetic mice and were reduced after ROS scavenger or p22(phox) downregulation in db(-)/db(-) mice. The present study showed that enhanced p22(phox) expression causes vascular dysfunction through ERK1/2 and p38-mitogen-activated protein kinase-dependent mechanisms in male type 2 diabetic mice. Therefore, p22(phox) could be an important target to improve vascular function in diabetes.
Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, New Orleans, Louisiana;
Modar
M
Kassan
Soo-Kyoung
SK
Choi
Maria
M
Galán
Young-Ho
YH
Lee
Mohamed
M
Trebak
Khalid
K
Matrougui
D000818:Animals; D003331:Coronary Vessels / Q000201:enzymology / Q000503:physiopathology; D003573:Cytochrome b Group / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000378:metabolism; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D003573:Cytochrome b Group; D016166:Free Radical Scavengers; D034741:RNA, Small Interfering; D014665:Vasodilator Agents; D019255:NADPH Oxidases; C515614:Cyba protein, mouse; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases
NADPH; endothelium-dependent relaxation; p22phox; type 2 diabetes