Coinduction of endothelial nitric oxide synthase and arginine recycling enzymes in aorta of diabetic rats.
Decreased availability of arginine and impaired production of NO (nitric oxide) have been implicated in the development of endothelial dysfunction. Citrulline formed by the NOS reaction is recycled to arginine by the citrulline-NO cycle, which is composed of NOS, argininosuccinate synthetase (AS), and argininosuccinate lyase. Therefore, we investigated the alterations of these enzymes in the aorta of streptozotocin (STZ)-induced diabetic rats. eNOS and AS mRNAs were increased by three- to fourfold 1-2 weeks after STZ treatment and decreased at 4 weeks. AL mRNA was weakly induced. Induction of eNOS and AS proteins was also observed. Cationic amino acid transporter (CAT)-1 mRNA remained little changed, and CAT-2 mRNA was not detected. The plasma nitrogen oxide levels were increased 1-2 weeks after STZ treatment and decreased at 4 weeks. Transforming growth factor-beta1 (TGF-beta1) mRNA in the aorta was also induced. TGF-beta1 induced eNOS and AS mRNAs in human umbilical vein endothelial cells but inhibited the proliferation of HUVEC. These results indicate that eNOS and AS are coinduced in the aorta in early stages of STZ-induced diabetic rats and that the induction is mediated by TGF-beta1. The results also suggest that TGF-beta1 works antiatherogenically at early stages of diabetes by increasing NO production, whereas prolonged elevation of TGF-beta1 functions atherogenically by inhibiting endothelial cell growth.
Oyadomari
S
S
Department of Molecular Genetics, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan.
Gotoh
T
T
Aoyagi
K
K
Araki
E
E
Shichiri
M
M
Mori
M
M
D026923:Amino Acid Transport Systems, Basic; D000818:Animals; D001011:Aorta / Q000201:enzymology*; D001120:Arginine / Q000378:metabolism*; D001123:Argininosuccinate Lyase / Q000235:genetics; D001124:Argininosuccinate Synthase / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000097:blood; D008099:Liver / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology; D014471:Umbilical Veins
D026923:Amino Acid Transport Systems, Basic; D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; D008565:Membrane Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D001120:Arginine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D001123:Argininosuccinate Lyase; D001124:Argininosuccinate Synthase