Role of Arginase in Selective Impairment of Endothelium-Dependent Nitric Oxide Synthase-Mediated Dilation of Retinal Arterioles during Early Diabetes
Role of Arginase in Selective Impairment of Endothelium-Dependent Nitric Oxide Synthase-Mediated Dilation of Retinal Arterioles during Early Diabetes
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DOI：
10.1167/iovs.61.5.36
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发表时间：
2020-05-01
影响因子：
4.4
通讯作者：
Kuo, Lih
中科院分区：
文献类型：
--
作者：
Hein, Travis W.;Omae, Tsuneaki;Kuo, Lih
目的。视网膜血管运动活性受一氧化氮合酶(NOS)和环氧合酶(COX)两种主要内皮酶的调节。血管精氨酸酶也消耗一氧化氮合酶底物，从而阻碍一氧化氮合酶介导的血管扩张。糖尿病表现为视网膜血管并发症，氧化应激升高，一氧化氮合酶介导的血管扩张功能受损。然而，潜在的分子机制仍不清楚，糖尿病对COX介导的血管扩张的影响也不清楚。方法：从链佐菌素诱导的糖尿病猪(2周高血糖，433+/-27 mg/dL)或年龄匹配的对照组猪(97+/-4 mg/dL)分离视网膜小动脉。结果：糖尿病2周后，视网膜小动脉对组胺和组胺的扩张作用明显减弱。一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯(L-NAME)可减弱对照组血管对组胺的扩张，但不能减弱糖尿病血管对组胺的扩张。在L-NAME和环氧合酶抑制剂消炎痛的存在下，对照组和糖尿病患者的组胺诱导的血管扩张作用相似。用精氨酸酶抑制剂NOR-NOHA治疗糖尿病血管，而不用超氧化物歧化酶类似物TEMPOL，以L名字敏感的方式同时保护组胺和缓激肽诱导的血管扩张。结论：糖尿病时，精氨酸酶而不是超氧化物削弱内皮依赖的一氧化氮合酶介导的视网膜小动脉扩张，而COX介导的血管扩张保持不变。阻断血管精氨酸酶可改善糖尿病早期视网膜小动脉的内皮功能。
PURPOSE. Retinal vasomotor activity can be regulated by two major endothelial enzymes, nitric oxide synthase (NOS) and cyclooxygenase (COX). The vascular arginase also consumes a NOS substrate and thus impedes NOS-mediated vasodilation. Diabetes mellitus exhibits vascular complications in the retina with elevated oxidative stress and compromised NOS-mediated vasodilation. However, the underlying molecular mechanisms remain unclear, and the effect of diabetes on COX-mediated vasodilation is unknown. Herein, we examined the relative impact of diabetes on retinal arteriolar dilations to COX and NOS activation and the roles of arginase and superoxide in diabetes-induced vasomotor dysfunction.METHODS. Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2 weeks of hyperglycemia, 433 +/- 27 mg/dL) or age-matched control pigs (97 +/- 4 mg/dL). The vasodilations to bradykinin (NOS activator) and histamine (NOS/COX activator) were examined in vitro.RESULTS. Retinal arteriolar dilations to histamine and bradykinin were significantly reduced after 2 weeks of diabetes. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) attenuated the dilations of control vessels, but not diabetic vessels, to histamine. In the presence of L-NAME and COX inhibitor indomethacin, histamine-induced dilations of control and diabetic vessels were reduced similarly. Treatment of diabetic vessels with arginase inhibitor nor-NOHA, but not superoxide dismutase mimetic TEMPOL, preserved both histamine- and bradykinin-induced dilations in an L-NAME-sensitive manner.CONCLUSIONS. Arginase, rather than superoxide, impairs endothelium-dependent NOS-mediated dilation of retinal arterioles during diabetes, whereas vasodilation mediated by COX remains intact. Blockade of vascular arginase may improve endothelial function of retinal arterioles during early onset of diabetes.