2) 一酸化窒素-Arginase代謝系による動脈硬化の発症・防御機構とエストロゲンの関与(シンポジウム1:女性ヘルスケア「中高年に対する女性医学の展開」,第64回日本産科婦人科学会・学術講演会)

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  • 尾林,聰
    東京医科歯科大学大学院生殖機能協関学

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  • Defensive Mechanism against Atherosclerosis through Nitric Oxide (NO)-Arginase System, Including Participation of Estrogen

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The mechanism to occur intimal hyperplasia is complex and poorly understood, but it is well established that dysfunction in endothelium is one of the important mechanisms to cause atherosclerosis. Nowadays, endothelium-derived nitric oxide (NO) is recognized as the key factor to regulate atherosclerosis. NO mediates vasodilation, inhibits platelet adhesion and aggregation, monocyte adhesion and smooth muscle cell proliferation and endothelin-1 production, which have potential impact to inhibit intimal hyperplasia. NO is generated from L-arginine as substrate through the activation of NO synthase (NOS) and NOS activity is regulated through the accumulation of endogenous NOS inhibitors. Additionally, L-arginine is metabolized to L-ornithine through the activation of enzyme, arginase and this signal pathway induced intimal hyperplasia, in turn. This NO - arginase pathway has a great impact on regulating not only NO release, but also smooth muscle cell proliferation, and is present as strong endothelium derived inhibitor of atherosclerosis. In this research, human uterine arteries (UA) were utilized as the specimen acquired during benign gynecological operations and ascending UA were used to reveal the inhibiting mechanism for atherosclerosis. After informed consent, UA specimens were collected after removing the surrounding connective tissue and cut into 3mm width. All the patients had regular menstruation cycle and were otherwise healthy, normotensiye and were with no medication. 1) To identify the releasing potential of NO in UA, isometric tension change were examined to vertical UA stretched with resting tension of 1g in 37℃ modified Krebs solution bubbled with 95% O_2 and 5% CO_2 for the stable pH. One end of each strip was secured to the bottom of the organ chamber and the other end was connected to a force-displacement transducer. Under pre-contraction of norepinephrine (NE: 10^<-6>M), acetylcholine (Ach: 10^<-9>-10^<-5>M) induced endothelium dependent relaxation (EDR) which consisted of NO and relaxing prostaglandin in normal pathological specimens (group I). On the other hand, specimens with intimal hyperplasia (group II) showed no relaxation response which indicated close relationship between the decrease of NO release and intimal hyperplasia. Additionally, the maximum % relaxation induced by Ach showed positive correlation with estradiol concentration of the patients, which suggested the regulatory mechanism to UA endothelial function with estradiol. A23187, calcium ionophre also evoked EDR in UA strip, but regulation of estradiol was not observed in group I, suggesting the regulation of muscarinic Ach receptor level with estradiol. 2) In endothelial cells, NO release is controlled by endogenous NOS inhibitors, monomethyl arginine (L-NMMA) and asymmetric dimethyl arginine (ADMA). To clarify the participation of NOS inhibitors in UA, HPLC was applied. Endothelium in group II UA indicated the increase of inhibitors without changing NOS activity. Furthermore, the content of endothelin-1 (ET-1) , a potent accelerator of smooth muscle cell proliferation and intimal hyperplasia, showed positive correlation to inhibitors tissue content which showed a positive correlation to intima media ratio, again. Taken together, these data suggested that increased NOS inhibitors reduced NO release which induce ET-1 in turn and finally evoked intimal hyperplasia. 3) L-arginine worked as a substrate of NO and. was metabolized to L-ornithine by arginase in endothelium, which suggested the occurrence of intimal thickening by a decreased NO release through the arginase activation. Arginase also induces the accumulation of proline and polyamines which accelerate extracellular matrix deposition and the smooth muscle cell proliferation. Therefore, the activation of arginase induced intimal hyperplasia through the decrease of NO release and accelerated the formation of hyperplasia in smooth muscle layer. UA specimen in group II revealed the enhanced arginase activity than group I, in both endothelium and smooth muscle layer. Western blotting in group II revealed enhanced protein expression of arginase I and II in endothelium, and enhanced expression of arginase II in smooth muscle layer. These results suggested that enhanced activity of arginase and enhanced expression of arginase protein in group It UA may result in intimal thickening. 4) Ach released both NO and PG in UA endothelium and the interaction of these factors was investigated. Either sodium nitroprusside (SNP) as NO donor or iloprost (IP) as stable PGI2 analogue was applied to UA strips and the minimum concentration which evoked the smallest relaxation was defined as Cmin. After the determination of Cmin of SNP or IP, simultaneous application of both agents was performed to the same strip, and relaxation response and cyclic nucleotides content were measured. In normal specimens of group I, an observed relaxation was significantly greater than predicted and the increases in cyclic nucleotides contents were also interacted synergistically. But this interaction was not observed in group H. On the other hand, applied Cmins and single dose increase in cyclic nucleotides were not different in two groups. These results suggested this synergism was the fundamental phenomenon to maintain normal pathological structure in group I, and the attenuation of the synergism might be related to enhance intimal hyperplasia in UA.

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