Arginase inhibition restores in vivo coronary microvascular function in type 2 diabetic rats
Arginase inhibition restores in vivo coronary microvascular function in type 2 diabetic rats
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DOI：
10.1152/ajpheart.00560.2010
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发表时间：
2011-04-01
影响因子：
4.8
通讯作者：
Pernow, John
中科院分区：
文献类型：
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作者：
Gronros, Julia;Jung, Christian;Pernow, John
Gronros J、Jung C、Lundberg JO、Cerrato R、Ostenson C、Pernow J。精氨酸酶抑制可恢复 2 型糖尿病大鼠体内冠状动脉微血管功能。 Am J Physiol Heart Circ Physiol 300：H1174-H1181，2011。首次发表于 2011 年 2 月 4 日； doi:10.1152/ajpheart.00560.2010.-一氧化氮 (NO) 对于维持正常的内皮功能和血管完整性至关重要。糖尿病中精氨酸酶活性的增加可能会与一氧化氮合酶 (NOS) 竞争共同底物精氨酸，从而导致一氧化氮 (NO) 的产生减少。本研究的目的是利用体内冠状动脉血流速度储备（CFVR）评估2型糖尿病Goto-Kakizaki（GK）大鼠的冠状动脉微血管功能以及精氨酸酶抑制恢复血管功能的效果。不同组的 GK 和 Wistar 大鼠分别给予载体、精氨酸酶抑制剂 N-omega-羟基-去甲-L-精氨酸 (nor-NOHA)、L-精氨酸和 NOS 抑制剂 N-G-单甲基-L-精氨酸 (L-NMMA)。与 Wistar 大鼠相比，GK 大鼠的 CFVR 受损（1.31 +/- 0.09 与 1.87 +/- 0.05，P < 0.001）。与 GK 大鼠中的媒介物相比，nor-NOHA 治疗可恢复 CFVR（1.71 +/- 0.13 与 1.23 +/- 0.12，P < 0.05），但 Wistar 大鼠中 CFVR 保持不变（1.88 +/- 0.10 与 1.79 +/- 0.16）。 NOS 抑制后，nor-NOHA 对 GK 大鼠的有益作用被消除。与媒介物相比，CFVR 不受精氨酸的影响。与 Wistar 大鼠相比，GK 大鼠的主动脉和心肌中的精氨酸酶 II 表达增加。在nor-NOHA治疗后，GK大鼠血浆中瓜氨酸与鸟氨酸和瓜氨酸与精氨酸的比率比Wistar大鼠显着增加，表明精氨酸利用从精氨酸酶转向NOS。总之，2型糖尿病GK大鼠的冠状动脉微血管功能受损。 Nor-NOHA 治疗通过与 NOS 对精氨酸的利用增加和 NO 可用性增加相关的机制恢复微血管功能。
Gronros J, Jung C, Lundberg JO, Cerrato R, Ostenson C, Pernow J. Arginase inhibition restores in vivo coronary microvascular function in type 2 diabetic rats. Am J Physiol Heart Circ Physiol 300: H1174-H1181, 2011. First published February 4, 2011; doi:10.1152/ajpheart.00560.2010.-Nitric oxide (NO) is crucial for maintaining normal endothelial function and vascular integrity. Increased arginase activity in diabetes might compete with NO synthase (NOS) for their common substrate arginine, resulting in diminished production of NO. The aim of this study was to evaluate coronary microvascular function in type 2 diabetic Goto-Kakizaki (GK) rats using in vivo coronary flow velocity reserve (CFVR) and the effect of arginase inhibition to restore vascular function. Different groups of GK and Wistar rats were given vehicle, the arginase inhibitor N-omega-hydroxy-nor-L-arginine (nor-NOHA), L-arginine, and the NOS inhibitor N-G-monomethyl -L-arginine (L-NMMA). GK rats had impaired CFVR compared with Wistar rats (1.31 +/- 0.09 vs. 1.87 +/- 0.05, P < 0.001). CFVR was restored by nor-NOHA treatment compared with vehicle in GK rats (1.71 +/- 0.13 vs. 1.23 +/- 0.12, P < 0.05) but remained unchanged in Wistar rats (1.88 +/- 0.10 vs. 1.79 +/- 0.16). The beneficial effect of nor-NOHA in GK rats was abolished after NOS inhibition. CFVR was not affected by arginine compared with vehicle. Arginase II expression was increased in the aorta and myocardium from GK rats compared with Wistar rats. Citrulline-to-ornithine and citrulline-to-arginine ratios measured in plasma increased significantly more in GK rats than in Wistar rats after nor-NOHA treatment, suggesting a shift of arginine utilization from arginase to NOS. In conclusion, coronary artery microvascular function is impaired in the type 2 diabetic GK rat. Treatment with nor-NOHA restores the microvascular function by a mechanism related to increased utilization of arginine by NOS and increased NO availability.