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Acceleration of intinul hyperplasia by the enhanced arginase activity due to hyperglycemia

高血糖导致精氨酸酶活性增强，加速血管内增生

基本信息

批准号：
14572152
负责人：
AZUMA Hiroshi
金额：
$ 2.18万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572152/
关键词：
Hyperglycemia Acceleration of intimal hyperplasia Enhanced arginase activity Endogenous NOS inhibitors Endogenous arginase inhibitor Polyamines Aldose reductase Ornithine decarboxylase Ornithine aminotransferase 内膜肥厚増悪 arginase活性亢進 N

项目摘要

Intimal hyperplasia, which is induced following endothelial denudation of the rabbit carotid artery, was accelerated by hyperglycemia caused by alloxan. The accelerated intimal hyperplasia was associated with (1)the decreased activity of dimethylarginine dimethylaminohydrolase (DDAH), which is a metabolizing enzyme of the endogenous NOS inhibitors, (2)accelerated accumulation of endogenous NOS inhibitors in regenerated endothelial cells, (3)enhanced arginase activity and (4)accelerated activity of aldose reductase. Since L-arginine is a common substrate for arginase and NOS, the greatly increased arginase activity may lead to the decreased NO production although NOS activity itself was increased. Furthermore, accumulation of endogenous NOS inhibitors and decreased L-arginine content possibly relate to the decreased NO production. Meanwhile, accelerated consumption of NADPH by the enhanced aldose reductase appeared to result in the impaired NO generation, since NADPA is a common cofacto … More r for aldose reductase and NOS. There was a negative correlationshp between NO production and magnitude of intimal hyperplasia, that is, the magnitude of intimal hyperplasia became greater as NO production was decreased. In addition, the magnitude of internal hyperplasia became greater as concentrations of endogenous inhibitors were increased in regenerated endothelial cells, which had probably been brought about by the decreased DDAH activity. N^G hydroxy-L-arginine (NOHA) as an intermediate of NO production from L-arginine inhibited arginase in a concentration-dependent manner with IC_<50> value of 2.1±0.1 mM, suggesting that the decreased NOHA due to decreased NO production probably brings about the increased arginase activity and further decrease in NO production. The increased activities of omithine decarboxylase (ODC) and omithine amonitrasferase (OAT) due to hyperglycemia resulted in the increased production of putrescine and proline, respectively. The former is well known as a potent mitogen and the latter as a material of collagen production. All these changes may closely relate to acceleration of intimal hyperplasia following endothelial denudation under the hyperglycemia. Less

四氧嘧啶引起的高血糖可加速兔颈动脉内皮剥脱后内膜增生。内膜增生的加速与内源性NOS抑制剂的代谢酶二甲基精氨酸二甲氨基水解酶（DDAH）活性降低、内源性NOS抑制剂在再生内皮细胞中的积累加速、血管生成酶活性增强和醛糖还原酶活性增强有关。由于L-精氨酸是精氨酸酶和NOS的共同底物，因此，尽管NOS活性本身增加，但精氨酸酶活性的显著增加可能导致NO产生的减少。内源性NOS抑制剂的积累和L-精氨酸含量的降低可能与NO产生的减少有关。与此同时，由于NADPA是一种常见的共同因素，增强的醛糖还原酶加速消耗NADPH似乎会导致NO生成受损 ...更多信息 r为醛糖还原酶和NOS。NO生成量与内膜增生程度呈负相关，即NO生成量减少，内膜增生程度加重。此外，内部增生的幅度变得更大的内源性抑制剂的浓度增加，在再生的内皮细胞，这可能是由DDAH活性降低所带来的。N^G-羟基-L-精氨酸（NOHA）作为L-精氨酸合成NO的中间产物，以浓度依赖的方式抑制NO合成酶的活性，IC<50>值为2.1± 0.1mM，表明NO合成减少导致NOHA降低可能导致NO合成酶活性增加，进而导致NO合成减少。高血糖引起的鸟氨酸脱羧酶（ODC）和鸟氨酸氨硝转移酶（OAT）活性的增加分别导致腐胺和脯氨酸的产生增加。前者是众所周知的作为一种有效的有丝分裂原和后者作为胶原蛋白生产的材料。这些变化可能与高血糖状态下内皮剥脱后内膜增生加速有关。少