雌激素受体GPR30对老年绝经后冠状动脉内皮功能衰竭的调节及其对雌激素替代疗法改进的初步研究

Estrogen replacement therapy had no effect to coronary heart disease of post-menopausal women.It is important to find improved methods。By enhancing BH4 levels to increase eNOS coupling and promoting secretion of NO inhibition of iNOS，estrogen protect blood vessels. But,the role of estrogen changes accompanying environmental changes. In the aging state,changed the role of estrogen has a relationship with HRT failure. So,increased express of iNOS and eNOS uncoupling in aging artery endothelial could not be suppressed. Estrogen receptor GPR30 is a new discovery. We found that GPR30 improve diabetes endothelial dysfunction through eNOS/NO signaling pathway. Recent studies have found that anti-inflammatory effect of GPR30 was canceled by ERα/β. Thus we put forward our hypothesis GPR30 regulates the expression of iNOS and eNOS uncoupling in aging artery endothelial,finally improves coronary endothelial dysfunction in postmenopause.But,the protective effects of GPR30 can be canceled by HRT.In this study, experiments were done at the cellular level and the level of body. GPR30 gene knockout and shRNA are established. We use vascular perfusion, PCR, Western-blot to investigate the mechanisms of GPR30 in improving coronary endothelial dysfunction in postmenopause.The present study aims to provide new ideas of HRT program for the prevention and treatment of coronary heart disease of post-menopausal women.

雌激素替代疗法(HRT)对老年女性绝经后冠心病无防治作用,找到改良方法是当务之急。雌激素提高动脉内皮BH4含量促eNOS偶联及抑制iNOS分泌NO,保护血管,但随环境状态不同其作用会发生变化。HRT的失败可能与雌激素作用发生改变无法抑制衰老动脉内皮iNOS高表达、eNOS解偶联有关。GPR30是新发现的第三类雌激素受体。我们发现GPR30通过eNOS/NO途径改善糖尿病内皮功能障碍。最新报道称GPR30抗炎作用被传统雌激素受体抵消。激动GPR30是否可增高BH4含量,降低iNOS表达改善老年绝经后冠状动脉内皮功能衰竭，但在HRT中该作用被雌激素诱导的其他效应所抵消呢？本项目通过细胞/动物两个层面，借助siRNA转染和GPR30敲除手段,应用血管灌流、PCR、Western-blot研究GPR30对衰老内皮功能及相关信号通路的影响。为制定以选择性激动GPR30为核心的改良HRT提供理论支持。

雌激素替代疗法(HRT)对老年女性绝经后冠心病无防治作用,找到改良方法是当务之急。GPR30是新发现的第三类雌激素受体。该受体对老年绝经后冠状动脉的影响目前还处于探索阶段。本项目通过动物/细胞两个层面研究GPR30对衰老内皮功能及相关信号通路的影响。我们研究发现选择性激动GPR30所发挥的冠状动脉内皮保护作用可伴随雌性机体的衰老逐渐减退，甚至观察到反作用趋势。在衰老机体内环境状态下阻断传统雌激素受体及雄激素受体可部分恢复GPR30的内皮保护作用。从而改善衰老个体的心脏功能。同时结合细胞层面研究，证实选择性激动雌激素受体GPR30使冠状动脉内皮iNOS表达下降、BH4水平增高以及超氧阴离子水平降低，从而改善老年绝经后冠状动脉内皮功能衰竭，达到改善老年绝经后心功能的作用，而其冠状动脉内皮保护作用可被绝经后衰老机体内环境改变所导致雌激素负反应及雄激素作用所抵消。同时发现食物来源的芹菜素可激动GPR30发挥生物作用。总之，我们的发现为更加深入地认识目前HRT的弊端，为制定以选择性激动雌激素受体GPR30为核心的改良HRT提供理论支持。