Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
Am J Physiol Heart Circ Physiol. 2011 Mar;300(3):H777-83. doi: 10.1152/ajpheart.00831.2010. Epub 2011 Jan 7.
Arginase 1, via competing with nitric oxide (NO) synthase for the substrate L-arginine, may interfere with NO-mediated vascular responses. We tested the hypothesis that arginase 1 contributes to coronary vasomotor dysfunction in patients with diabetes mellitus (DM). Coronary arterioles were dissected from the right atrial appendages of 41 consecutive patients with or without DM (the 2 groups suffered from similar comorbidities), and agonist-induced changes in diameter were measured with videomicroscopy. We found that the endothelium-dependent agonist ACh elicited a diminished vasodilation and caused constriction to the highest ACh concentration (0.1 μM) with a similar magnitude in patients with (18 ± 8%) and without (17 ± 9%) DM. Responses to ACh were not significantly affected by the inhibition of NO synthesis with N(G)-nitro-L-arginine methyl ester in either group. The NO donor sodium nitroprusside-dependent dilations were not different in patients with or without DM. Interestingly, we found that the presence of N(G)-hydroxy-L-arginine (10 μM), a selective inhibitor of arginase or application of L-arginine (3 mM), restored ACh-induced coronary dilations only in patients with DM (to 47 ± 6% and to 40 ± 19%, respectively) but not in subjects without DM. Correspondingly, the protein expression of arginase 1 was increased in coronary arterioles of patients with DM compared with subjects without diabetes. Moreover, using immunocytochemistry, we detected an abundant immunostaining of arginase 1 in coronary endothelial cells of patients with DM, which was colocalized with NO synthase. Collectively, we provided evidence for a distinct upregulation of arginase 1 in coronary arterioles of patients with DM, which contributes to a reduced NO production and consequently diminished vasodilation.
精氨酸酶 1 通过与一氧化氮 (NO) 合酶竞争底物 L-精氨酸，可能会干扰 NO 介导的血管反应。我们检验了一个假说，即精氨酸酶 1 可能导致糖尿病患者的冠状动脉血管舒缩功能障碍。我们从 41 例连续患者（有或没有糖尿病）的右心耳中分离出冠状动脉小动脉，并使用视频显微镜测量激动剂诱导的直径变化。我们发现，内皮依赖性激动剂 ACh 引起的血管舒张减弱，并且在相同的程度上引起最大 ACh 浓度（0.1 μM）的收缩。在有（18 ± 8%）和没有（17 ± 9%）糖尿病的患者中，ACh 的反应没有明显受到 N(G)-硝基-L-精氨酸甲酯对 NO 合成的抑制的影响。在有或没有糖尿病的患者中，NO 供体硝普钠依赖性扩张没有差异。有趣的是，我们发现，存在 N(G)-羟基-L-精氨酸（10 μM），一种精氨酸酶的选择性抑制剂，或应用 L-精氨酸（3 mM），仅在糖尿病患者中恢复 ACh 诱导的冠状动脉扩张（分别为 47 ± 6%和 40 ± 19%），但在没有糖尿病的患者中没有。相应地，与没有糖尿病的患者相比，糖尿病患者的冠状动脉小动脉中的精氨酸酶 1 蛋白表达增加。此外，通过免疫细胞化学，我们在糖尿病患者的冠状动脉内皮细胞中检测到大量的精氨酸酶 1 免疫染色，其与 NO 合酶共定位。总的来说，我们提供了证据表明，糖尿病患者的冠状动脉小动脉中精氨酸酶 1 的表达明显上调，导致 NO 产生减少，进而血管舒张减弱。
