Accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, attenuated dimethylarginine dimethylaminohydrolase activity and intimal hyperplasia in premenopausal human uterine arteries.
The present study was designed to investigate the involvement of nitric oxide synthase (NOS), endogenous NOS inhibitors, arginase, which shares L-arginine as a common substrate with NOS, and dimethylarginine dimethylaminohydrolase (DDAH) as a metabolizing enzyme of NOS inhibitors in the occurrence of intimal hyperplasia in premenopausal human uterine arteries. Fifty-two uterine arteries were obtained from 52 patients undergoing total hysterectomy with an informed consent for the present study. All specimens were assessed histologically and the intima:media ratio (%) was evaluated as an index of intimal hyperplasia. Nineteen specimens were found to be histologically normal (intima:media ratio=16.1+/-0.8%), whereas remaining 33 specimens were categorized as intimal hyperplasia (intima:media ratio=34.4+/-1.5%). The intimal hyperplasia was associated with the impaired cyclic GMP production without change in endothelial NOS activity per se, accumulation of endogenous NOS inhibitors in endothelial cells, attenuated DDAH activity in endothelial cells and enhanced arginase activity in endothelial cells and smooth muscle layer. These findings suggest that the impaired cyclic GMP production as a marker of NO production is possibly due to the accumulated endogenous NOS inhibitors and enhanced arginase activity, which, in turn, closely relates to the occurrence of intimal hyperplasia, and that the impaired DDAH activity would result in the accumulation of endogenous NOS inhibitors in endothelial cells. Because of the enhanced arginase activity in endothelial cells and smooth muscle layer, the accelerated polyamine biosynthetic pathway may be implicated in the occurrence of intimal hyperplasia in premenopausal human uterine arteries.
Loyaga-Rendon
Renzo Y
RY
Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8519, Japan.
Sakamoto
Shuichi
S
Beppu
Masashi
M
Aso
Takeshi
T
Ishizaka
Mihoko
M
Takahashi
Ryoko
R
Azuma
Hiroshi
H
D000328:Adult; D000581:Amidohydrolases / Q000494:pharmacology*; D001119:Arginase / Q000494:pharmacology*; D001158:Arteries / Q000473:pathology; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D006965:Hyperplasia; D007044:Hysterectomy; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D017697:Premenopause; D017539:Tunica Intima / Q000473:pathology*; D014599:Uterus / Q000098:blood supply*
D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; D001119:Arginase; C059999:dimethylargininase