Bif-1通过Ca2+/calcineurin信号通路调控心肌肥大的作用和分子机制研究

Our previous studies evidenced the effect of endophilin A2 in cardiovascular system. However, the effect of Bif-1 in cardiovascular system remains elusive. Our primary data showed that Bif-1 was expressed in cardiomyocytes and myocardial tissues abundantly, and it obviously increased in hypertrophic myocardial tissues. Knockdown of Bif-1 inhibited the increased cell surface area, Ca2+/calcineurin activity and GRP-78 expression induced by angiotensin II. Moreover, Bif-1 could bind to IP3R. Our present study aimed to further clarify the interaction between Bif-1 and IP3R, and how this interaction interferes with Ca2+/calcineurin signaling pathway and thus induces cardiac hypertrophy. Moreover, we will investigate the functional role of Bif-1 in cardiac hypertrophy in C57 mice. This work will reveal the new function of Bif-1 in heart diseases. It raises the possibility that Bif-1 is a key regulator of Ca2+/calcineurin signaling pathway, suggesting that Bif-1 may be a novel therapeutic target for cardiac hypertrophy.

我们的前期研究证实了endophilin A2在心血管系统中的作用，但另一亚型Bif-1在心血管系统中的功能尚不清楚。预实验结果发现，Bif-1在心肌细胞及心肌组织中表达丰富，并且在肥大心肌组织中表达显著升高。沉默Bif-1可抑制angiotensin II诱导的心肌细胞表面积增加、Ca2+/calcineurin信号通路活化以及GRP78表达增加。进一步研究发现，Bif-1与IP3R相互结合。本研究拟在上述工作基础上，阐明Bif-1结合IP3R进而调控Ca2+/calcineurin信号通路，诱导心肌肥大的分子机制。并通过在体实验检测Bif-1对心肌肥大的影响。该工作将从一个新的角度阐明Bif-1在心脏疾病中的作用，提出Bif-1可能是调控Ca2+/calcineurin信号通路关键分子的新观点，并为评估Bif-1是否可作为防治心肌肥大的新靶点提供实验室依据。

本课题从Bif-1调控急性心梗后心肌损伤角度开展了相关研究，主要发现有：1. 急性心梗心脏梗死周边区，心肌细胞Bif-1表达升高；2. 氧糖剥夺处理的原代乳鼠心肌细胞，Bif-1表达升高；3. 心肌下调Bif-1改善急性心梗后心肌损伤；4. 心肌上调Bif-1加剧急性心梗后心肌损伤；5. 下调Bif-1通过改善心脏脂质代谢，抑制ER stress，减轻心梗后心肌损伤。我们的研究结果揭示了Bif-1表达上调是急性心梗后心肌损伤的关键病理生理机制，阐明了Bif-1是调控心脏脂质代谢及ER stress关键分子。这些工作从一个全新的角度揭示了急性心梗后心肌损伤的产生机制，为治疗心肌损伤提供了新的治疗靶点。