Moretto Johnny, Guglielmetti Anne-Sophie, Tournier-Nappey Maude, Martin Hélène, Prigent-Tessier Anne, Marie Christine, Demougeot Céline
PEPITE EA4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France.
INSERM U1093, Univ. Bourgogne Franche-Comté, F-21000, Dijon, France.
Exp Gerontol. 2017 Apr;90:52-60. doi: 10.1016/j.exger.2017.01.023. Epub 2017 Jan 26.
While ageing is frequently associated with l-arginine deficiency, clinical and experimental studies provided controversial data on the interest of a chronic l-arginine supplementation with beneficial, no or even deleterious effects. It was hypothesized that these discrepancies might relate to a deviation of l-arginine metabolism towards production of l-ornithine rather than nitric oxide as a result of age-induced increase in arginase activity. This study investigated the effect of ageing on arginase activity/expression in target tissues and determined whether l-arginine supplementation modulated the effect of ageing on arginase activity. Arginase activity and expression were measured in the heart, vessel, brain, lung, kidney and liver in young rats (3-months old) and aged Wistar rats (22-24-months-old) with or without l-arginine supplementation (2.25% in drinking water for 6weeks). Plasma levels of l-arginine and l-ornithine were quantified in order to calculate the plasma l-arginine/l-ornithine ratio, considered as a reflection of arginase activity. Cardiovascular parameters (blood pressure, heart rate) and aortic vascular reactivity were also studied. Ageing dramatically reduced plasma l-arginine and l-arginine/l-ornithine ratio, decreased liver and kidney arginase activities but did not change activities in other tissues. l-Arginine supplementation normalized plasma l-arginine and l-arginine/l-ornithine ratio, improved endothelial function and decreased systolic blood pressure. These effects were associated with decreased arginase activity in aorta along with no change in the other tissues except in the lung in which activity was increased. A strong mismatch was therefore observed between arginase activity and expression in analyzed tissues. The present study reveals that ageing selectively changes arginase activity in clearance tissues, but does not support a role of the arginase pathway in the potential deleterious effect of the l-arginine supplementation in aged patients. Moreover, our data argue against the use of the measurement of plasma l-arginine/l-ornithine ratio to estimate arginase activity in aged patients.
虽然衰老常与L-精氨酸缺乏相关，但临床和实验研究对于长期补充L-精氨酸的益处、无影响甚至有害影响提供了有争议的数据。据推测，这些差异可能与精氨酸酶活性随年龄增长而增加导致L-精氨酸代谢偏向于生成L-鸟氨酸而非一氧化氮有关。本研究调查了衰老对靶组织中精氨酸酶活性/表达的影响，并确定补充L-精氨酸是否能调节衰老对精氨酸酶活性的影响。在年轻大鼠（3个月大）和老年Wistar大鼠（22 - 24个月大）的心脏、血管、脑、肺、肾和肝脏中测量精氨酸酶活性和表达，这些大鼠分别补充或不补充L-精氨酸（饮用水中含2.25%，持续6周）。对血浆中L-精氨酸和L-鸟氨酸水平进行定量，以计算血浆L-精氨酸/L-鸟氨酸比值，该比值被视为精氨酸酶活性的反映。还研究了心血管参数（血压、心率）和主动脉血管反应性。衰老显著降低了血浆L-精氨酸和L-精氨酸/L-鸟氨酸比值，降低了肝脏和肾脏的精氨酸酶活性，但未改变其他组织中的活性。补充L-精氨酸使血浆L-精氨酸和L-精氨酸/L-鸟氨酸比值恢复正常，改善了内皮功能并降低了收缩压。这些作用与主动脉中精氨酸酶活性降低相关，其他组织中除肺组织活性增加外无变化。因此，在所分析的组织中观察到精氨酸酶活性与表达之间存在强烈的不匹配。本研究表明，衰老选择性地改变了清除组织中的精氨酸酶活性，但不支持精氨酸酶途径在老年患者补充L-精氨酸的潜在有害作用中起作用。此外，我们的数据反对使用测量血浆L-精氨酸/L-鸟氨酸比值来估计老年患者的精氨酸酶活性。
