vinexin对心肌肥厚发生发展的影响及其机制的研究

Cardiac hypertrophy, an enlargement and fibrosis of the heart caused by hypertension, myocardial infarction, can cause heart failure ,arrhythmias and sudden death. Although many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppressing hypertrophic remodeling remian largely unexplored. .We focus on a novel ubiquitously expressed cell adhesion protein, vinexin. Vinexin, expressed at high levels in the heart, is a cytoplasmic and nucleus molecule of the integrin-containing cell adhesion complex. Its principal role has been determined in the regulation of cell adhesion, cytoskeletal organization and regulation of signal transduction. However, the cardiac effect of vinexin in hypertrophy has not been well understood. .Our preliminary results indicated that vinexin may play an important role in the hypertrophy. To investigate more fundamental aspects of vinexin function in hypertrophy, the first part of this research is that vinexin knockout mice (KO) and cardiac-specific vinexin transgenic mice (TG) are uesed to generate pressure overload-induced left ventricular hypertrophy. Furthermore, the second part of our research will use the primary cultures of KO and TG cardiac myocytes and fibroblasts to explore the roles of vinexin in hypertrophy..Here, we want to use KO and TG mice to investigate whether vinexin regulates cardiac hypertrophy in vitro and in vivo and elucidated the underlying molecular mechanisms, for looking for new targets for myocardial hypertrophy.

持久的心肌肥厚导致心力衰竭、恶性心律失常甚至猝死。Vinexin是细胞-胞外基质粘附蛋白，在细胞间信号传导中起着重要作用，但vinexin在心肌肥厚中的作用尚未明了。本实验室前期研究结果显示，vinexin在心肌肥厚患者心脏中蛋白表达增加，而且vinexin基因敲除小鼠心肌肥厚程度增大，提示vinexin可能参与心肌肥厚的发生发展过程。然而vinexin对心肌肥厚是否有作用以及其作用机理尚不明确。本项目拟用基因敲除和心脏特异性转基因小鼠建立心肌肥厚模型，研究vinexin基因对心肌肥厚的作用及可能的分子机制；然后拟用原代培养的小鼠心肌细胞及成纤维细胞，在细胞水平进一步探讨vinexin基因敲除或过表达对心肌细胞肥大、纤维化的影响，力图明确vinexin对心肌肥厚的影响，阐明其根本机制，为寻找治疗心肌肥厚新靶点提供新思路。

心肌肥厚是临床上许多心血管疾病包括高血压、心肌梗死、心律失常等共有的病理过程，长期持续性的心肌肥厚能够引起扩张性心肌病、心力衰竭甚至猝死。Vinexin是在细胞-胞外基质粘附中发现的一种新的蛋白。先前的研究已经表明，Vinexin-β表达较广泛，且在心脏中为高表达，但无关于Vinexin-β在心肌肥厚中的作用及其机制的报道。因此，为研究Vinexin-β在心肌肥厚的发生发展中所起的作用，我们用主动脉缩窄方法在Vinexin-β基因敲除小鼠及心脏特异性Vinexin-β转基因小鼠中建立心肌肥厚模型。使用超声心动图对心肌肥厚的程度进行评价，使用病理染色及分子生物学技术对心脏样品进行分析。我们的研究结果表明，Vinexin-β在心脏中显著抑制心肌肥厚、间质纤维化和心功能不全，而的敲除心脏中的Vinexin-β则加重了压力负荷引发的病理性心脏重构和纤维化。通过体外和体内的实验，进一步的研究表明其可能的作用机制如下：vinexin通过激活AKT/GSK3β信号通路，抑制FOX3A的表达，减轻心肌细胞的病理性肥大。