The effect of high glucose on NO and O2- through endothelial GTPCH1 and NADPH oxidase.
Although endothelial dysfunction deteriorates diabetic angiopathy, the mechanisms are obscure. We revealed that high glucose augmented eNOS through stimulation of eNOS mRNA in cultured BAECs. NO was decreased and O2- was increased simultaneously. NOS inhibitor, inhibited O2- release, so did NADPH oxidase inhibitor. The effects were synergistic. Both intracellular BH4 level and GTPCH1 activity were decreased by high glucose, in line with decrease of GTPCH1 mRNA. HMG-CoA reductase inhibitor, atorvastatin increased GTPCH1 mRNA and activity, and BH4 level. Conclusively, high glucose leads to eNOS dysfunction by inhibiting BH4 synthesis and atorvastatin stimulate BH4 synthesis directly, and it may work as atherogenic process.
Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Shawa-ku, Nagoya, 466-8550, Japan; Department of Geriatrics, the First University Hospital of West China University of Medical Sciences, Chengdu, China.
Qun Fang
QF
Ding
Toshio
T
Hayashi
A R Juliet
AR
Packiasamy
Asaka
A
Miyazaki
Akiko
A
Fukatsu
Hiroaki
H
Shiraishi
Takahide
T
Nomura
Akihisa
A
Iguchi
D000818:Animals; D000069059:Atorvastatin; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D015153:Blotting, Western; D002417:Cattle; D042783:Endothelial Cells / Q000187:drug effects*; D005434:Flow Cytometry; D006136:GTP Cyclohydrolase / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D001708:Biopterins; D009569:Nitric Oxide; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D006136:GTP Cyclohydrolase; C003402:sapropterin; D005947:Glucose; D010100:Oxygen