Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, M409 Medical Sciences Building, One Hospital Drive, Columbia, MO, 65212, USA.
College of Osteopathic Medicine, William Cary University, Hattiesburg, MS, USA.
Amino Acids. 2018 Jun;50(6):747-754. doi: 10.1007/s00726-018-2567-x. Epub 2018 Apr 27.
This study investigated the temporal activation of arginase in obese Zucker rats (ZR) and determined if arginase inhibition prevents the development of hypertension and improves insulin resistance in these animals. Arginase activity, plasma arginine and nitric oxide (NO) concentration, blood pressure, and insulin resistance were measured in lean and obese animals. There was a chronological increase in vascular and plasma arginase activity in obese ZR beginning at 8 weeks of age. The increase in arginase activity in obese animals was associated with a decrease in insulin sensitivity and circulating levels of arginine and NO. The rise in arginase activity also preceded the increase in blood pressure in obese ZR detected at 12 weeks of age. Chronic treatment of 8-week-old obese animals with an arginase inhibitor or L-arginine for 4 weeks prevented the development of hypertension and improved plasma concentrations of arginine and NO. Arginase inhibition also improved insulin sensitivity in obese ZR while L-arginine supplementation had no effect. In conclusion, arginase inhibition prevents the development of hypertension and improves insulin sensitivity while L-arginine administration only mitigates hypertension in obese animals. Arginase represents a promising therapeutic target in ameliorating obesity-associated vascular and metabolic dysfunction.
这项研究调查了肥胖 Zucker 大鼠 (ZR) 中精氨酸酶的时间激活，并确定精氨酸酶抑制是否可预防这些动物高血压的发生和改善胰岛素抵抗。在瘦型和肥胖型动物中测量了精氨酸酶活性、血浆精氨酸和一氧化氮 (NO) 浓度、血压和胰岛素抵抗。从 8 周龄开始，肥胖 ZR 的血管和血浆精氨酸酶活性呈时间顺序增加。肥胖动物中精氨酸酶活性的增加与胰岛素敏感性降低以及循环精氨酸和 NO 水平降低有关。在 12 周龄检测到肥胖 ZR 血压升高之前，精氨酸酶活性的升高也先于其升高。用精氨酸酶抑制剂或 L-精氨酸对 8 周龄肥胖动物进行 4 周的慢性治疗可预防高血压的发生并改善血浆精氨酸和 NO 的浓度。精氨酸酶抑制还改善了肥胖 ZR 的胰岛素敏感性，而 L-精氨酸补充则没有效果。总之，精氨酸酶抑制可预防高血压的发生并改善胰岛素敏感性，而 L-精氨酸给药仅可减轻肥胖动物的高血压。精氨酸酶是改善肥胖相关血管和代谢功能障碍的有希望的治疗靶点。
