Bansal Seema, Chopra Kanwaljit
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.
Gen Comp Endocrinol. 2014 Sep 15;206:51-9. doi: 10.1016/j.ygcen.2014.06.013. Epub 2014 Jun 23.
Estrogen is known to influence vascular functions and insulin sensitivity, but the relative contribution of estrogen receptor (ER) isoforms in postmenopausal diabetes-induced vascular dysfunction is unclear. The aim of the present study was to delineate the distinct role of estrogen receptor-α and beta β on the vascular function in ovariectomized diabetic rats. Age matched 60 female sprague dawley rats (200-250g) were divided in nine groups. Bilateral ovariectomy was performed and streptozotocin was used to induce experimental diabetes. Rats were administered with 10μg/kg; s.c. of a nonselective estrogen receptor agonist, 17-β estradiol (E2), selective ER-α agonist (4,4',4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) tris phenol (PPT) and selective ER-β agonist, 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) for 4weeks after STZ injection. Treatment with selective ER-α agonist and E2 improved the impaired glycemic and lipid profile in ovariectomized diabetic rats, however selective ER-β agonist did not show any effect. Vascular endothelial dysfunction was assessed by acetylcholine and sodium nitroprusside-induced endothelium dependent and independent relaxation in isolated rat aortic ring preparation as well as by electron microscopy of thoracic aorta. Further, serum thiobarbituric acid reactive substances, tumour necrotic factor-alpha and interleukin-1 beta and C-reactive protein were estimated to assess oxidative stress and vascular inflammation. Treatment with ER-α agonist markedly and E2 partially improved vascular function and endothelial integrity along with reduction in serum TBARS and inflammatory cytokines. However, ER-β agonist did not show any improvement in vascular functions, oxidative stress or inflammation. These findings suggest that selective targeting of ER-α receptors results in vasculoprotection in the state of hypoestrogenicity and diabetes.
已知雌激素会影响血管功能和胰岛素敏感性，但雌激素受体（ER）亚型在绝经后糖尿病诱导的血管功能障碍中的相对作用尚不清楚。本研究的目的是阐明雌激素受体α和β在去卵巢糖尿病大鼠血管功能中的不同作用。将60只年龄匹配的雌性Sprague Dawley大鼠（200 - 250g）分为九组。进行双侧卵巢切除术，并用链脲佐菌素诱导实验性糖尿病。在注射链脲佐菌素后4周，给大鼠皮下注射10μg/kg的非选择性雌激素受体激动剂17-β雌二醇（E2）、选择性ER-α激动剂（4,4',4″-(4-丙基-[1H]吡唑-1,3,5-三基)三苯酚（PPT）和选择性ER-β激动剂2,3-双(4-羟基苯基)-丙腈（DPN）。选择性ER-α激动剂和E2治疗改善了去卵巢糖尿病大鼠受损的血糖和血脂状况，然而选择性ER-β激动剂未显示任何效果。通过乙酰胆碱和硝普钠诱导的离体大鼠主动脉环制备中的内皮依赖性和非依赖性舒张以及胸主动脉的电子显微镜检查来评估血管内皮功能障碍。此外，估计血清硫代巴比妥酸反应性物质、肿瘤坏死因子-α、白细胞介素-1β和C反应蛋白以评估氧化应激和血管炎症。用ER-α激动剂治疗可显著改善血管功能和内皮完整性，E2部分改善，同时血清硫代巴比妥酸反应物和炎性细胞因子减少。然而，ER-β激动剂在血管功能、氧化应激或炎症方面未显示任何改善。这些发现表明，在雌激素缺乏和糖尿病状态下，选择性靶向ER-α受体可实现血管保护。
