Enhanced p22~(phox) expression impairs vascular function through p38 and ERK1/2 MAP kinase-dependent mechanisms in type 2 diabetic mice

摘要

Type 2 diabetes is associated with vascular complication. We hypothesized that increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p22~(phox) expression impairs vascular endo-thelium-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 super-oxide dismutase (1,000 U/kg daily ip), or small interfering RNA p22~(phox) (p22~(phox)-lentivirus-small interfering RNA, 100 mug 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-acti-vated protein kinase-dependent mechanisms in male type 2 diabetic mice. Therefore, p22~(phox) could be an important target to improve vascular function in diabetes.