| Co-Investigator(Kenkyū-buntansha) |
WAKIMOTO Hiroko Tokyo Medical and Dental University, Faculty of Medicine, Junior Lecturer, 大学院・医歯学総合研究科, 助手 (60345296)
AZUMA Hiroshi Tokyo Medical and Dental University, Institute of Biomaterials and Bioengineering, Professor, 生体材料工学研究所, 教授 (20134736)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Endothelium-derived nitric oxide (NO) plays a critical role in pulmonary vascular remodeling associated with pulmonary hypertension. The results and interpretations in the present research using pulmonary hypertensive model were described below. 1, L-arginine (L-arg), a substrate of NO, concentration in pulmonary arterial endothelial cells (PAECs) was decreased because of the accelerated activity of arginase, a first enzyme of urea cycle. 2, Endogenous NO synthase (NOS) inhibitors, N^G-monomethyl-L-arginine (L-NMMA) and N^G, N^G-dimethyl-L-arginine (ADMA), concentration in PAECs was increased because of the attenuated activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme related to catabolism of NOS inhibitors. 3, Ornithine decarboxylase (ODC), an enzyme acting on ornithine, activity was increased, probably followed by the increased putrescine, a powerful mitogen of pulmonary vascular smooth muscle cells. 4, Endothelial NOS activity as well as its protein expression wer
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e increased. 5, Accelerated arginase activity was recovered by N^G-hydroxy L-arginine (NOHA), an intermediate metabolite synthesized from L-arg by NOS. Based on these results, we concluded that lack of arginase activity inhibition by NOHA, followed by potentiated L-arg consumption, can lead to decrease NO production as so-called vicious circle in PAECs. In the present study, we couldn't perform to examine another signal transduction pathway in the downstream of arginase. Proline is synthesized by ornithine aminotransferase (OAT) from ornithine, and a mitogen of collagen fibers mainly existed in the vascular adventitia. As the future direction of the present study, taking into the presence of vicious circle among NOS and arginase signal transduction pathways, we are focusing on the NOS inhibitors, which are associated with NO production at the upper stream and can be metabolically regulated by DDAH. Moreover, we consider the development of DDAH agonist, which is available under the clinical settings, and hope that the agonist will be used for the radical treatment of PH. Less
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