胆汁酸受体FXR基因敲除对压力超负荷诱导心肌肥厚及心脏功能影响的研究

The farnesoid X receptor is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. FXR, function as a metabolic regulator, plays key roles in bile acid, cholesterol, lipid and glucose metabolism. Previously studies showed that the expression of FXR was mainly expressed in the digestive system and cardiovascular system, but the function of FXR in heart diseases was still not clear. Our hypothesis is that there is a potential protective effect of FXR in pressure over-load induced cardiac hypertrophy. Our preliminary data showed that comparing to wild type mice, the FXR knockout mice after pressure overload induced cardiac hypertrophy model showed a significant increase in myocardial hypertrophy, hear weight/body weight ratio, myocardial cell volume, and the elevated expression of myocardial hypertrophy markers. Cardiac tissue infiltration of inflammatory cells, blood inflammatory cytokines secretion and cardiac fibrosis increased in FXR knockout mice than in wild type mice. These results suggest that the nuclear receptor FXR participates in cardiac adaptive hypertrophy and fibrosis during the process of cardiac remodeling under hypertrophic stress. Next, we explain the related mechanisms of FXR mediated signal pathway of myocardial protection.

法尼酯衍生物X受体(Farnesoid X Receptor，FXR)是核受体超家族的成员。FXR作为内源性胆汁酸受体广泛存在于消化系统中，最新的研究表明FXR在心肌细胞中也有表达，但FXR在心脏中的功能目前还不清楚。我们在前期研究中利用主动脉缩窄术构建压力超负荷诱导的心室重构模型，结果表明FXR敲除小鼠更加容易诱导出心肌肥厚加重、心肌细胞体积增大、心肌肥厚标志物和纤维化标志物表达升高，心脏组织中浸润的炎症细胞和炎症因子分泌也增高。据此我们提出FXR参与心肌细胞的保护的科学假说，并通过在压力超负荷诱导心肌肥厚过程中FXR作用机制来验证。我们的预实验结果显示FXR基因敲除导致压力负荷诱导的心肌肥厚加重和心脏功能下降。我们还将采用QPCR、免疫组化等方法进一步研究FXR对心脏功能保护的分子机制。本项目旨在阐明FXR介导心肌保护作用的信号通路及其相关机制研究，并为心力衰竭治疗提供新的药物靶点。

胆汁酸受体FXR是核受体超家族一员，参与调控糖脂代谢，肝脏再生，炎症和肝癌等。本课题主要想通过压力超负荷诱导心衰模型验证FXR是否参与心脏相关疾病过程。首先，通过主动脉结扎模型发现FXR基因敲除会导致相比野生型小鼠更加严重的心肌肥厚，纤维化和功能衰退。其次，我们还通过之前的研究发现FXR基因敲除小鼠心肌细胞糖脂代谢异常，于是再利用代谢性糖尿病心肌病模型发现FXR敲除会导致糖尿病心肌病脂质堆积更加严重，血糖也更高。最后，本研究还发现FXR基因敲除小鼠血管结构异常，利用颈动脉损伤模型研究FXR对血管功能调节。综上所述，FXR在心血管相关疾病存在重要的作用，其功能机制还需要深入探究，为其作为治疗心血管相关疾病潜在作用靶点奠定基础。