FGF6通过Hippo-YAP通路改善心肌缺血损伤的相关机制研究

Endogenous cardiomyocytes regeneration is an effective method to treat myocardial infarction. The feature that promotes cardiomyocytes regeneration makes FGF6 a potential drug for myocardial infarction treatment. In the previous study, we’ve demonstrated that FGF6 could lower the risks of myocardial infarction by stimulating the regeneration of cardiomyocytes. We further proved that FGF6 mediated cardiac protection is associated with its role in inhibiting Hippo pathway, thus enhancing YAP-Park2 transcription. However, the mechanism remains to be further explored. Thus, we will firstly confirm that FGF6 mediated Hippo pathway inhibition constitutes the main molecular basis for the cardiac protection after myocardial infarction through gene manipulated Hippo pathway persistent activation in the FGF6 overexpressed cardiaomyocytes and mice hearts. Secondly, the endogenous YAP will be replaced with its persistent phosphorylated form YAP (SD) in FGF6 overexpressed cardiaomyocytes and mice hearts. Thus verifying YAP is the main transcription factor in FGF6 exerted cardiac protection. Finally, Park2 will be deleted both in FGF6 overexpressed cardiaomyocytes and mice hearts. Thereby, confirming Park2 is the main effector protein underlying FGF6 mediated cardiac protection. The achievement of this research will not only provide a theoretical basis for clinical therapy but also exploit a new method for the treatment of myocardial infarction.

促内源性心肌细胞新生是治疗心肌梗死的有效手段，FGF6促细胞新生的特性使其有望成为治疗心肌梗死的潜在药物，但其调控机制尚不清楚。我们已在前期研究中证实FGF6可通过促进梗死心脏中心肌细胞的新生缓解心肌缺血损伤，并初步确认该效应与其抑制Hippo信号通路并增加YAP-Park2转录活性相关，但该机制有待更为详实的确证。基于前期研究，我们将首先在FGF6过表达的细胞及心脏中使Hippo通路持续激活，从而明确Hippo通路在FGF6发挥保护效应中的作用；随后在FGF6过表达的细胞及心脏中表达持续磷酸化的YAP，进而确证YAP作为主要转录因子参与FGF6的保护机制；最后在FGF6过表达的细胞及心脏中使Park2缺失，在细胞及动物层面证实Park2作为主要效应蛋白参与FGF6对心肌缺血损伤的保护效应。本项目旨在分子水平深入阐明FGF6改善心肌梗死的机理，并将为心肌梗死的防治提供新的策略和理论依据。

心血管疾病作为影响人类健康的三大疾病之一，而心肌梗死（MI）作为心血管疾病中最常见的一种，阻塞冠状动脉，影响机体给心脏本身的供血，致使患者病死率高，严重影响着人类生命健康。但目前心肌梗死的临床治疗策略仍局限于介入治疗，旨在减少心肌细胞的凋亡，但未能提出方案如何替代凋亡的心肌细胞行使其原本功能。本研究着重探讨FGF6通过Hippo信号通路途径增强缺血损伤后心肌细胞增殖潜能的作用。 .我们发现在MI小鼠模型中FGF6的表达显著升高。腺病毒干扰FGF6的MI小鼠与正常MI小鼠相比，心功能变差，心脏梗死面积更大，心脏切面的纤维化面积也明显高于MI小鼠。相比之下，注射人重组蛋白FGF6可以改善了心功能，减少了梗死面积，激活心肌细胞周期，使心肌细胞增殖，并促进了心脏修复。我们的研究结果证明，FGF6在心肌缺血条件下抑制Hippo通路的激活，进而促进YAP向细胞核内积聚，激活YAP下游转录翻译和细胞周期，促进细胞增殖。然而这一作用在很大程度上受ERK1/2影响，在使用ERK1/2抑制剂后，FGF6在缺血条件下促进心肌细胞增殖的能力大大降低。.综上所述，在心肌缺血条件下，FGF6在心肌细胞中的表达升高，外源性注射的FGF6蛋白后可以通过ERK1/2抑制Hippo通路中MST1，LATS1的磷酸化，进而抑制YAP的磷酸化，促使YAP向细胞核内转移，进入细胞核中的YAP激活细胞周期蛋白，从而促进心肌细胞在缺血条件下的增殖。