Administration of L-arginine plus L-citrulline or L-citrulline alone successfully retarded endothelial senescence.
Administration of L-arginine plus L-citrulline or L-citrulline alone successfully retarded endothelial senescence.
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DOI：
10.1371/journal.pone.0192252
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Hayashi T
中科院分区：
文献类型：
--
作者：
Tsuboi T;Maeda M;Hayashi T
已证明补充L-瓜氨酸和L-精氨酸对心血管系统有几种有益作用。一氧化氮（NO）可防止动脉粥样硬化的进展，由一氧化氮合酶（NOS）合成，将L-精氨酸（L-Arg）转化为L-瓜氨酸（L-Cit）。我们的前期研究表明，L-Cit和L-Arg联合长期给药对高胆固醇诱导的家兔动脉粥样硬化有较好的治疗作用。我们研究了L-Arg和L-Cit如何影响内皮功能、衰老和动脉粥样硬化。在用高葡萄糖（HG：22 mM）和L-Arg（300 μM）、L-Cit（300 μM）或L-Arg + L-Cit（LALC：各150 μM）补充物刺激人脐静脉内皮细胞（HUVEC）3天后，评价内皮衰老和功能。这些氨基酸也给予血脂异常2型糖尿病（ZDFM）大鼠喂食高胆固醇饮食。他们被喂食L-Arg或L-Cit或LALC四个星期。通过检测衰老相关β-半乳糖苷酶（SA-β-gal）、端粒酶活性、DNA损伤和p16 INK 4a蛋白表达来研究主动脉衰老。只有L-Cit和LALC补充延缓了HG诱导的内皮衰老，如通过SA-β-gal活性（一种广泛使用的细胞衰老标志物）、p16 INK 4a表达（一种衰老相关蛋白）和DNA损伤所评估的。在HG条件下，L-Cit和LCLA使端粒酶活性恢复到正常葡萄糖（NG）条件下观察到的水平。在HG条件下，L-Cit降低ROS产生，如通过CM-H2 DCFDA和p67 phox（NADPH氧化酶的主要组分）的表达所测量的。在HG条件下，L-Cit和LALC增加NO的产生，如通过EST-2AM所测量的。内皮型一氧化氮合酶（eNOS）和磷酸化eNOS在HG条件下降低，L-Cit和LALC显着增加这些水平。精氨酸酶2蛋白表达增加HG条件下，和L-Cit和LALC显着减弱这种影响。在ZDFM大鼠中，在主动脉内皮表面上检测到SA-β-gal活性;然而，L-Cit和LALC降低了这些水平。L-Cit和LALC均能降低衰老细胞的比例。此外，用LALC治疗4周增加了血浆NO的产生。因此，结论是，补充L-瓜氨酸通过抑制ROS产生和谷胱甘肽转移酶2蛋白表达，比补充L-精氨酸更好地挽救了NO水平。因此，L-Cit和LCLA补充延缓了HG诱导的内皮衰老。
L-citrulline and L-arginine supplementation has been shown to have several beneficial effects on the cardiovascular system. Nitric oxide (NO) protects against the progression of atherosclerosis and is synthesized by nitric oxide synthase (NOS), which converts L-arginine (L-Arg) into L-citrulline (L-Cit). Our previous study revealed that chronic administration of a combination of L-Cit and L- Arg has a better therapeutic effect on high cholesterol-induced atherosclerosis in rabbits. We investigated how L-Arg and L-Cit affect endothelial function, aging and atherosclerosis. Following a 3-day stimulation of human umbilical venous endothelial cells (HUVECs) with high glucose (HG: 22 mM) and L-Arg (300 μM), L-Cit (300 μM) or L-Arg plus L-Cit (LALC: each 150 μM) supplementation, endothelial senescence and function were evaluated. These amino acids were also administered to dyslipidemic type 2 diabetic (ZDFM) rats fed a high cholesterol diet. They were fed L-Arg or L-Cit or LALC for four weeks. Aortic senescence was investigated by measuring senescence-associated ß-galactosidase (SA-ß-gal), telomerase activity, DNA damage and p16INK4a protein expression. Only L-Cit and LALC supplementation retarded the HG-induced endothelial senescence, as evaluated by SA-ß-gal activity, a widely used marker of cellular senescence, p16INK4a expression, a senescence-related protein, and DNA damage. Under HG conditions, L-Cit and LCLA restored telomerase activity to levels observed under normal glucose (NG) conditions. Under HG conditions, L-Cit decreased ROS production, as measured by CM-H2DCFDA and the expression of p67phox, a major component of NADPH oxidase. Under HG conditions, L-Cit and LALC increased NO production, as measured by DAF-2AM. Endothelial NO synthase (eNOS) and phosphorylated eNOS were decreased under HG conditions and L-Cit and LALC significantly increased these levels. Arginase 2 protein expression increased under the HG conditions, and L-Cit and LALC significantly attenuated this effect. In ZDFM rats, SA-ß-gal activity was detected on the aortic endothelial surface; however, L-Cit and LALC reduced these levels. L-Cit and LALC both decreased the proportion of senescent cells. Furthermore, treatment with LALC for 4 weeks increased plasma NO production. Therefore conclusively, L-citrulline supplementation rescued NO levels better than L-arginine supplementation by inhibiting ROS production and arginase 2 protein expression. Consequently, L-Cit and LCLA supplementation retaeded HG-induced endothelial senescence.
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DOI：
10.1073/pnas.0603918103
发表时间：
2006-07-05
影响因子：
11.1
作者：
Hayashi, Toshio;Esaki, Teiji;Chaudhuri, Gautam
通讯作者：
Chaudhuri, Gautam
影响因子：
3.7
作者：
Maeda M;Hayashi T;Mizuno N;Hattori Y;Kuzuya M
通讯作者：
Kuzuya M
影响因子：
4.8
作者：
Goodwin, BL;Solomonson, LP;Eichler, DC
通讯作者：
Eichler, DC
影响因子：
5.3
作者：
Haendeler, J;Hoffmann, J;Dimmeler, S
通讯作者：
Dimmeler, S
影响因子：
5.3
作者：
HAYASHI, T;ISHIKAWA, T;KUZUYA, F
通讯作者：
KUZUYA, F