雌激素加重肾血管性高血压形成的机制研究

Essential hypertension is one of the most common cardiovascular disease, which is one of the risk factors of cardiovascular and cerebrovascular diseases increased morbidity and mortality. Its pathogenesis is perplexing, of which the most important is the renin-angiotensin system ( RAS ) activation, especially of RAS in local tissue has a detrimental effect on cardiovascular function.Estrogen has protective effects on the cardiovascular system. As for the relationship between estrogen and RAS, each laboratory income out of the experimental result is different. Our study found that plasma AngⅡ of female spontaneously hypertensive rats was positively correlated with the concentration of serum estrogen.10-week-old SD rats were prepared by the narrow side of the renal artery to development renovascular hypertension (2K1C).After removal of both ovaries of a group of female rats (VOX)， 2K1C operation was performed in female rats. Compared with 2K1C-male rats, blood pressure were significantly higher in 2K1C-female rats and similar in 2K1C-OVX rats . This project aims to dynamically observe the effect of estrogen on different postoperative time points in rat blood pressure and the function of heart.To illustrate the mechanism of estrogen how sensitized the effect of RAS and promoted the formation of renal vascular hypertension,using quantitative real-time polymerase chain reaction determined the mRNA levels of angiotensinogen, renin, ACE, ACE2, AT1, AT2 （RAS）in local tissue. Western Blot method was used to detect the protein expression of local tissue RAS. Observe the change of oxidative stress related factors.Application of estrogen receptor knockout mice for preparing 2K1C hypertension，In order to study the role of estrogen is to play through which receptor subtypes.

原发性高血压是最常见的心血管疾病之一，是造成诸多心脑血管疾病发病率和死亡率增加的危险因素之一。其发病机制错综复杂，其中最为重要的是肾素-血管紧张素系统（RAS）的激活，尤其是局部组织中的RAS对心血管功能产生有害的作用。雌激素对心血管系统有一定的保护作用。至于雌激素与RAS之间的关系，不同实验室所得出了的研究结果有一定的差异。我们研究发现雌性自发性高血压大鼠血清雌二醇浓度与血浆AngⅡ的浓度呈显著正相关；雌性二肾一夹（2K1C）大鼠血压水平比雄性大鼠高；去势导致雌激素水平低下后，血压水平接近雄性大鼠。本项目拟进一步动态观察雌激素对术后不同时间点的大鼠血压水平、心功能及局部组织RAS各组分的mRNA和蛋白质表达的影响，检测氧化应激相关因子的变化，以阐明雌激素增敏RAS促进肾血管性高血压形成的机制；应用雌激素受体基因敲除小鼠制备2K1C高血压，以确定该作用是何种雌激素受体亚型介导。

原发性高血压是最常见的心血管系统疾病之一，是造成诸多心脑血管疾病发病率和死亡率增加的危险因素之一。肾素-血管紧张素系统（RAS）的激活是高血压的重要发病机制之一，尤其是局部组织中的 RAS 对心血管功能产生有害的作用。雌激素对心血管系统有一定的保护作用。至于雌激素与 RAS 之间的关系，不同实验室所得出了的研究结果有一定的差异。本项目以肾血管性高血压大鼠为研究对象，观察性别及卵巢切除手术对高血压发生发展的作用及对局部组织中RAS的影响。研究结果表明雌性组（2K1C-F），形成的肾血管性高血压血压水平明显高于雄性组（2K1C-M），双侧卵巢切除导致雌激素水平低下时（2K1C-OVX），其血压水平明显下降，并且接近雄性大鼠的血压水平。高血压大鼠靶器官损伤的大体观察结果显示，2K1C-F组心肌肥厚和肾脏损伤程度及氧化应激损伤程度明显高于2K1C-M组和2K1C-OVX组；血浆AngII的含量明显低于2K1C-M组，ET-1的含量明显高于2K1C-M组。RAS各组分mRNA表达的结果显示，主动脉组织中2K1C-F组的Angiotensinogen和MAS基因的相对表达量明显高于2K1C-M组，ACE1、ACE2、AT1a和AT1b基因的相对表达量明显低于2K1C-M组，2K1C-OVX组的ACE1、ACE2、AT1a和AT1b基因的相对表达量明显高于2K1C-F组；心脏组织中2K1C-F组的ACE2、AT2，MAS基因的相对表达量明显高于2K1C-M组，Renin、ACE1、AT1a和AT1b基因的相对表达量明显低于2K1C-M组，2K1C-OVX组的ACE1基因的相对表达量明显高于2K1C-F组；肾脏组织中ACE2、AT2 和MAS基因的相对表达量明显高于2K1C-M组， ACE1、AT1a和AT1b基因的相对表达量明显低于2K1C-M组，2K1C-OVX组的Renin、和MAS基因的相对表达量明显低于2K1C-F组。RAS各组分蛋白表达的结果与mRNA表达一致， 2K1C-F组ACE1- AngII-AT1表达量低于2K1C-M组，ACE2- Ang1-7-MAS表达量高于2K1C-M组。结论：雌性大鼠肾血管性高血压的血压水平及靶器官损伤明显高于雄性，这种性别差异性不依赖于肾素血管紧张素系统的激活