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

四氧嘧啶引起的高血糖加速了兔颈动脉内皮剥脱后引起的内膜增生。内源性一氧化氮合酶抑制物代谢酶--二甲精氨酸二甲氨基水解酶(DDAH)活性降低，内源性一氧化氮合酶抑制物在再生内皮细胞内积聚加快，精氨酸酶活性增强，醛糖还原酶活性加快。由于L-精氨酸是精氨酸酶和一氧化氮合酶的共同底物，尽管一氧化氮合酶本身的活性增加，但精氨酸酶活性的大幅增加可能导致一氧化氮的产生减少。此外，内源性一氧化氮合酶抑制物的蓄积和L精氨酸含量的降低可能与NO的生成减少有关。同时，由于NADPA是一种常见的事实上的…，增强的醛糖还原酶加速了对NADPH的消耗，似乎导致了NO生成的受损醛糖还原酶和一氧化氮合酶有较高的r。NO生成量与内膜增生程度呈负相关，即随着NO生成量的减少，内膜增生程度加重。此外，随着再生内皮细胞中内源性抑制物浓度的增加，内皮细胞的增生程度也变得更大，这可能是由于DDAH活性降低所致。N^G羟基-L-精氨酸(NOHA)作为L精氨酸产生NO的中间体，对精氨酸酶的抑制作用呈浓度依赖性，IC_(50)为2.1±0.1 mM，提示NO产生减少可能导致精氨酸酶活性升高，NO产生进一步减少。高血糖引起的ODC和OAT活性升高分别导致腐胺和脯氨酸的产生增加。前者是众所周知的一种强有力的有丝分裂原，而后者是一种产生胶原的材料。这些变化可能与高血糖下内皮剥脱后内膜加速增殖密切相关。较少

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