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GPER inhibits diabetes-mediated RhoA activation to prevent vascular endothelial dysfunction.
European Journal of Cell Biology ( IF 6.6 ) Pub Date : 2016-01-21 , DOI: 10.1016/j.ejcb.2015.12.002 Zilin Li 1 , Liang Cheng 2 , Hongliang Liang 2 , Weixun Duan 2 , Jing Hu 3 , Weiwei Zhi 2 , Jinbao Yang 2 , Zhenhua Liu 2 , Minggao Zhao 4 , Jincheng Liu 2
European Journal of Cell Biology ( IF 6.6 ) Pub Date : 2016-01-21 , DOI: 10.1016/j.ejcb.2015.12.002 Zilin Li 1 , Liang Cheng 2 , Hongliang Liang 2 , Weixun Duan 2 , Jing Hu 3 , Weiwei Zhi 2 , Jinbao Yang 2 , Zhenhua Liu 2 , Minggao Zhao 4 , Jincheng Liu 2
Affiliation
The effect of estrogen receptors on diabetes-induced vascular dysfunction is critical, but ambiguous. Individuals with diabetic vascular disease may require estrogen receptor-specific targeted therapy in the future. The G protein-coupled estrogen receptor (GPER) has beneficial effects on vascular function. However, its fundamental mechanisms are unclear. The RhoA/Rho-kinase pathway contributes to diabetic vascular complications, whereas estrogen can suppress Rho-kinase function. Thus, we assumed that GPER inhibits diabetes-mediated RhoA activation to prevent vascular dysfunction. We further investigated the underlying mechanisms involved in this process. Vascular endothelial cells and ex vivo cultured ovariectomized (OVX) C57BL/6 mouse aortae were treated with high glucose (HG) alone or in combination with GPER agonist (G1). G1 treatment was also administered to OVX db/db mice for 8 weeks. An ex-vivo isovolumic myograph was used to analyze the endothelium-dependent vasodilation and endothelium-independent contraction of mouse aortae. Apoptosis, oxidative stress, and inflammation were attenuated in G1-pretreated vascular endothelial cells. G1 significantly decreased the phosphorylation of inhibitory endothelial nitric oxide (NO) synthase residue threonine 495 (eNOS Thr495), inhibited RhoA expression, and increased NO production. Additionally, G1 rescued the impaired endothelium-dependent relaxation and inhibited RhoA activation in the thoracic aorta of OVX db/db mice and ex-vivo cultured OVX C57BL/6 mouse aortae treated with HG. Estrogens acting via GPER could protect vascular endothelium, and GPER activation might elicit ERα-independent effect to inhibit RhoA/Rho-kinase pathway. Additionally, GPER activation might reduce vascular smooth muscle contraction by inhibiting RhoA activation. Thus, the results of the present study suggest a new therapeutic paradigm for end-stage vascular dysfunction by inhibiting RhoA/Rho-kinase pathway via GPER activation.
中文翻译:
GPER抑制糖尿病介导的RhoA活化,以预防血管内皮功能障碍。
雌激素受体对糖尿病引起的血管功能障碍的作用至关重要,但尚不明确。糖尿病血管疾病患者将来可能需要雌激素受体特异性靶向治疗。G蛋白偶联雌激素受体(GPER)对血管功能有有益作用。但是,其基本机制尚不清楚。RhoA / Rho激酶途径有助于糖尿病血管并发症,而雌激素可抑制Rho激酶功能。因此,我们假设GPER抑制糖尿病介导的RhoA活化,从而预防血管功能障碍。我们进一步研究了该过程涉及的潜在机制。血管内皮细胞和离体培养的卵巢切除(OVX)C57BL / 6小鼠主动脉分别用高葡萄糖(HG)或与GPER激动剂(G1)结合处理。还对OVX db / db小鼠进行了G1处理8周。体外等容肌电图用于分析小鼠主动脉的内皮依赖性血管舒张和内皮依赖性收缩。在经过G1处理的血管内皮细胞中,细胞凋亡,氧化应激和炎症反应减弱。G1显着降低了抑制性内皮一氧化氮(NO)合酶残基苏氨酸495(eNOS Thr495)的磷酸化,抑制了RhoA表达,并增加了NO的产生。此外,G1挽救了OVX db / db小鼠和经HG处理的离体培养OVX C57BL / 6小鼠主动脉胸主动脉受损的内皮依赖性舒张功能,并抑制了RhoA活化。通过GPER作用的雌激素可以保护血管内皮,GPER激活可能引起ERα非依赖性抑制RhoA / Rho激酶途径。另外,GPER激活可通过抑制RhoA激活来减少血管平滑肌收缩。因此,本研究的结果通过抑制经由GPER激活的RhoA / Rho激酶途径,提出了一种终末期血管功能障碍的新治疗范例。
更新日期:2015-12-29
中文翻译:
GPER抑制糖尿病介导的RhoA活化,以预防血管内皮功能障碍。
雌激素受体对糖尿病引起的血管功能障碍的作用至关重要,但尚不明确。糖尿病血管疾病患者将来可能需要雌激素受体特异性靶向治疗。G蛋白偶联雌激素受体(GPER)对血管功能有有益作用。但是,其基本机制尚不清楚。RhoA / Rho激酶途径有助于糖尿病血管并发症,而雌激素可抑制Rho激酶功能。因此,我们假设GPER抑制糖尿病介导的RhoA活化,从而预防血管功能障碍。我们进一步研究了该过程涉及的潜在机制。血管内皮细胞和离体培养的卵巢切除(OVX)C57BL / 6小鼠主动脉分别用高葡萄糖(HG)或与GPER激动剂(G1)结合处理。还对OVX db / db小鼠进行了G1处理8周。体外等容肌电图用于分析小鼠主动脉的内皮依赖性血管舒张和内皮依赖性收缩。在经过G1处理的血管内皮细胞中,细胞凋亡,氧化应激和炎症反应减弱。G1显着降低了抑制性内皮一氧化氮(NO)合酶残基苏氨酸495(eNOS Thr495)的磷酸化,抑制了RhoA表达,并增加了NO的产生。此外,G1挽救了OVX db / db小鼠和经HG处理的离体培养OVX C57BL / 6小鼠主动脉胸主动脉受损的内皮依赖性舒张功能,并抑制了RhoA活化。通过GPER作用的雌激素可以保护血管内皮,GPER激活可能引起ERα非依赖性抑制RhoA / Rho激酶途径。另外,GPER激活可通过抑制RhoA激活来减少血管平滑肌收缩。因此,本研究的结果通过抑制经由GPER激活的RhoA / Rho激酶途径,提出了一种终末期血管功能障碍的新治疗范例。