Shatanawi Alia, Momani Munther S, Al-Aqtash Ruaa, Hamdan Mohammad H, Gharaibeh Munir N
Department of Pharmacology, School of Medicine, The University of Jordan, Amman, Jordan.
Department of Internal Medicine, School of Medicine, The University of Jordan, Amman, Jordan.
Front Pharmacol. 2020 Dec 22;11:584669. doi: 10.3389/fphar.2020.584669. eCollection 2020.
Type 2 diabetes mellitus (T2DM) is becoming a major contributor to cardiovascular disease. One of the early signs of T2DM associated cardiovascular events is the development of vascular dysfunction. This dysfunction has been implicated in increasing the morbidity and mortality of T2DM patients. One of the important characteristics of vascular dysfunction is the impaired ability of endothelial cells to produce nitric oxide (NO). Additionally, decreases in the availability of NO is also a major contributor of this pathology. NO is produced by the activity of endothelial NO synthase (eNOS) on its substrate, L-arginine. Reduced availability of L-arginine to eNOS has been implicated in vascular dysfunction in diabetes. Arginase, which metabolizes L-arginine to urea and ornithine, competes directly with NOS for L-arginine. Hence, increases in arginase activity can decrease arginine levels, reducing its availability to eNOS and decreasing NO production. Diabetes has been linked to elevated arginase and associated vascular endothelial dysfunction. We aimed to determine levels of plasma NO and arginase activity in (T2DM) patients and the effects of L-citrulline supplementation, a natural arginase inhibitor, on inhibiting arginase activity in these patients. Levels of arginase correlated with HbA1c levels in diabetic patients. Twenty-five patients received L-citrulline supplements (2000 mg/day) for 1 month. Arginase activity decreased by 21% in T2DM patients after taking L-citrulline supplements. Additionally, plasma NO levels increased by 38%. There was a modest improvement on H1Ac levels in these patients, though not statistically significant. The effect of L-citrulline on arginase activity was also studied in bovine aortic endothelial cells (BAECs) grown in high glucose (HG) conditions. HG (25 mM, 72 h) caused a 2-fold increase in arginase activity in BAECs and decreased NO production by 30%. L-citrulline (2.5 mM) completely prevented the increase in arginase activity and restored NO production levels. These data indicate that L-citrulline can have therapeutic benefits in diabetic patients through increasing NO levels and thus maintaining vascular function possibly through an arginase inhibition related pathway.
2型糖尿病（T2DM）正成为心血管疾病的主要促成因素。T2DM相关心血管事件的早期迹象之一是血管功能障碍的出现。这种功能障碍与T2DM患者发病率和死亡率的增加有关。血管功能障碍的一个重要特征是内皮细胞产生一氧化氮（NO）的能力受损。此外，NO可用性的降低也是这种病理状态的主要促成因素。NO是由内皮型一氧化氮合酶（eNOS）作用于其底物L-精氨酸产生的。L-精氨酸对eNOS可用性的降低与糖尿病中的血管功能障碍有关。精氨酸酶将L-精氨酸代谢为尿素和鸟氨酸，它直接与一氧化氮合酶竞争L-精氨酸。因此，精氨酸酶活性的增加会降低精氨酸水平，减少其对eNOS的可用性并降低NO的产生。糖尿病与精氨酸酶升高及相关的血管内皮功能障碍有关。我们旨在测定（T2DM）患者血浆NO水平和精氨酸酶活性，以及天然精氨酸酶抑制剂L-瓜氨酸补充剂对这些患者精氨酸酶活性的抑制作用。糖尿病患者中精氨酸酶水平与糖化血红蛋白（HbA1c）水平相关。25名患者接受了为期1个月的L-瓜氨酸补充剂（2000毫克/天）。服用L-瓜氨酸补充剂后，T2DM患者的精氨酸酶活性下降了21%。此外，血浆NO水平升高了38%。这些患者的糖化血红蛋白（H1Ac）水平有适度改善，尽管无统计学意义。还在高糖（HG）条件下培养的牛主动脉内皮细胞（BAECs）中研究了L-瓜氨酸对精氨酸酶活性的影响。HG（25毫摩尔，72小时）使BAECs中的精氨酸酶活性增加了2倍，并使NO产生减少了30%。L-瓜氨酸（2.5毫摩尔）完全阻止了精氨酸酶活性的增加并恢复了NO产生水平。这些数据表明，L-瓜氨酸可能通过增加NO水平，从而可能通过与精氨酸酶抑制相关的途径维持血管功能，对糖尿病患者具有治疗益处。
