Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Biomedical Dental Sciences, College of Dentistry, University of Dammam, Dammam, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Eur J Pharmacol. 2017 Jul 15;807:44-55. doi: 10.1016/j.ejphar.2017.04.031. Epub 2017 Apr 22.
The renin angiotensin system (RAS) regulates numerous systemic functions and is expressed locally in skeletal tissues. Angiotensin1-7 (Ang1-7) is a beneficial member of the RAS, and the therapeutic effects of a large number of angiotensin receptors blockers (ARBs) are mediated by an Ang1-7-dependent cascade. This study examines whether the reported osteo-preservative effects of losartan are mediated through the angiotensin converting enzyme2 (ACE-2)/Ang1-7/Mas pathway in ovariectomized (OVX) rats. Sham and OVX animals received losartan (10mg/kg/d p.o.) for 6 weeks. A specific Mas receptor blocker (A-779) was delivered via mini-osmotic pumps during the losartan treatment period. Serum and urine bone metabolism biomarker levels were measured. Bone trabecular and cortical morphometry were quantified in distal femurs, whereas mineral contents were estimated in ashed bones, serum and urine. Finally, the expression of RAS components, the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) was determined. Losartan significantly improved the elevated bone metabolism marker levels and altered trabecular and cortical structures in OVX animals, and restored normal urinary and skeletal mineral levels. Mas receptor inhibition significantly abolished all osteo-protective effects of losartan and enhanced the deleterious effects of OVX. Losartan enhanced OVX-induced up-regulation of ACE-1, AngII, angiotensin type 1 (AT) receptor and RANKL expression, and increased ACE-2, Ang1-7, Mas and OPG expression in OVX animals. However, A-779 significantly eradicated the effects of losartan on RAS components and RANKL/OPG expression. Thus, Ang1-7 are involved in the osteo-preservative effects of losartan via Mas receptor, which may add therapeutic value to this well-known antihypertensive agent.
肾素血管紧张素系统（RAS）调节许多全身功能，并在骨骼组织中局部表达。血管紧张素 1-7（Ang1-7）是 RAS 的有益成员，大量血管紧张素受体阻滞剂（ARB）的治疗效果是通过 Ang1-7 依赖级联介导的。本研究检查了报告的氯沙坦的骨保护作用是否通过血管紧张素转换酶 2（ACE-2）/Ang1-7/Mas 途径在卵巢切除（OVX）大鼠中介导。假手术和 OVX 动物接受氯沙坦（10mg/kg/d p.o.）治疗 6 周。在氯沙坦治疗期间，通过微型渗透泵给予特定的 Mas 受体阻滞剂（A-779）。测量血清和尿液骨代谢生物标志物水平。在远端股骨中定量骨小梁和皮质形态计量学，而在灰化骨骼、血清和尿液中估计矿物质含量。最后，测定 RAS 成分、核因子-κB 配体（RANKL）和骨保护素（OPG）的表达。氯沙坦显著改善了 OVX 动物升高的骨代谢标志物水平和改变的小梁和皮质结构，并恢复了正常的尿和骨骼矿物质水平。Mas 受体抑制显著消除了氯沙坦的所有骨保护作用，并增强了 OVX 的有害作用。氯沙坦增强了 OVX 诱导的 ACE-1、AngII、血管紧张素 1（AT）受体和 RANKL 表达的上调，并增加了 OVX 动物的 ACE-2、Ang1-7、Mas 和 OPG 表达。然而，A-779 显著消除了氯沙坦对 RAS 成分和 RANKL/OPG 表达的影响。因此，Ang1-7 通过 Mas 受体参与氯沙坦的骨保护作用，这可能为这种著名的降压药物增加治疗价值。
