Vascular NADH oxidase is involved in impaired endothelium-dependent vasodilation in OLETF rats, a model of type 2 diabetes.
Superoxide anion can modulate vascular smooth muscle tone and is potentially involved in diabetic vascular complications. The present study was undertaken to characterize both vascular production and the enzymatic source of superoxide anion in type 2 diabetic rats. In the thoracic aorta of OLETF rats, endothelium-dependent relaxation was markedly attenuated compared with that of control (LETO) rats in association with a significant increase in superoxide production (2,421.39 +/- 407.01 nmol x min(-1) x mg(-1)). The increased production of superoxide anion was significantly attenuated by diphenyleneiodonium (DPI; 10 micromol/l), an inhibitor of NAD(P)H oxidase. The production of superoxide anion in response to NADH as a substrate was markedly increased in the vascular homogenates, but NADPH, arachidonic acid, xanthine, and succinate produced only small increases in chemiluminescence. In line with these results, studies using various enzyme inhibitors, such as DPI, allopurinol, rotenone, N(G)-monomethyl-L-arginine, and indomethacin, suggest that the predominant source of superoxide anion in vascular particulate fraction is NADH-dependent membrane-bound oxidase. Furthermore, the expression of p22phox, a major component of vascular NAD(P)H oxidase, was markedly increased in the aorta from OLETF rats compared with that of LETO rats. These findings suggest that upregulated expression of p22phox mRNA and enhanced NADH oxidase activity contribute to the impaired endothelium-dependent vasodilation in OLETF rats.
Kim
Yong K
YK
Department of Internal Medicine and Pharmacology, College of Medicine, Pusan National University, Pusan, South Korea.
Lee
Mi-S
MS
Son
Seok M
SM
Kim
In J
IJ
Lee
Won S
WS
Rhim
Byung Y
BY
Hong
Ki W
KW
Kim
Chi D
CD
D000818:Animals; D001808:Blood Vessels / Q000201:enzymology*; D003600:Cytosol / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D026901:Membrane Transport Proteins; D008566:Membranes / Q000201:enzymology; D009097:Multienzyme Complexes / Q000502:physiology*; D009247:NADH, NADPH Oxidoreductases / Q000502:physiology*; D009252:NADPH Dehydrogenase / Q000235:genetics; D019255:NADPH Oxidases; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010088:Oxidoreductases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF / Q000502:physiology*; D012016:Reference Values; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology*
D026901:Membrane Transport Proteins; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D012333:RNA, Messenger; D013481:Superoxides; D010088:Oxidoreductases; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase