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

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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