线粒体动力学介导心肌细胞肥大的力学生物学机制研究

Sustained pressure overload is known to trigger cardiac hypertrophy. Imbalance of mitochondrial dynamics, the processes of mitochondrial fusion and fission that determine mitochondrial morphology and quality, has been implicated in the underlying pathophysiology of cardiac hypertrophy. However, the mechanic biological mechanism of mitochondrial dynamics in cardiomyocytes hypertrophy induced by pressure overload remains unclear. The processes of mitochondrial fusion and fission are primarily regulated by mitofusins (Mfn1/2), optic atrophy protein 1 (OPA1) and dynamin related protein 1 (Drp1). Activities of Mfns, OPA1 and Drp1 are regulated by protein structure changes, post-translational modifications or even translocations. Our previous experiments have demonstrated that, mechanical stretch that induced cardiomyocytes hypertrophy leads to the phosphorylation and translocation of Mfn2. Therefore, the study is designed to test the hypothesis that, the key proteins controlling the processes of mitochondrial fusion and fission, might function as intracellular mechanoreceptors that could sense and transduce the mechanical stimulation.The dynamic structure or functional modification of these proteins might impair mitochondrial function, and finally leads to cardiac hypertrophy. Mechanical stretch will be applied to primary rat cardiomyocytes to induce hypertrophic phenotype, and the changes in structure, post-translational modification and translocation of the mitochondrial dynamics regulating proteins, as well as mitochondrial function will be detected. Furthermore, cardiac hypertrophy will be induced in rats by abdominal aortic constriction. Cardiac hypertrophy and abnormalities in mitochondrial fusion and fission, as well as the changes of the mitochondrial dynamics markers would then be analyzed in rats hearts. Taken together, this study might provide a novel insight for the mechanism of mechanical overload-induced cardiomyocytes hypertrophy and provide new therapeutic targets for the treatment of cardiac hypertrophy.

线粒体动力学失衡参与了压力超负荷所致心肌细胞肥大过程，但其力学生物学调控机制尚未阐明。研究表明Mfn1/2、OPA1、Drp1等线粒体动力学蛋白可通过结构改变、翻译后修饰、转位等被激活，并调控线粒体融合-分裂过程。在我们前期实验中观察到牵张力学刺激使心肌细胞Mfn2发生转位及磷酸化修饰，且这些改变与线粒体损伤一致。在本项目中我们提出“线粒体动力学蛋白是一类新的细胞内力学感受器，力学刺激可使其结构功能改变并激活其下游通路，从而导致心肌细胞肥大”的假设。为此，本项目拟以线粒体动力学为研究对象，用不同的方法证实力学刺激可改变或修饰线粒体动力学调控蛋白分子结构，促发线粒体动力学失衡，引起心肌细胞肥大。同时通过大鼠腹主动脉缩窄模型，观察由压力超负荷引起心肌肥厚大鼠的心肌组织中，这些蛋白是否发生改变，以证实上述假设。从而为力学超负荷所致心肌细胞肥大的机制提出全新观点；可望为其临床治疗提供新的靶标。

超负荷条件下的力学牵张刺激是诱导心肌细胞肥大的始动因素之一。线粒体动力学失衡可能参与了压力超负荷所致心肌细胞肥大过程，但其中的力学生物学调控机制尚未阐明。因此，本研究的主要目的是证实线粒体动力学相关蛋白（如Drp1及Mfn2）是一类新的细胞内力学感受器，并探索其结构功能是否因力学刺激而发生动态改变，同时激活其下游通路，从而导致心肌细胞肥大。 .我们通过动物学实验及细胞生物力学等实验，证实了压力超负荷所致的心肌细胞肥大过程中，线粒体动力学失衡，使其分裂增加、融合减少，导致碎片化的线粒体增加。压力超负荷还通过对Drp1及Mfn2等蛋白进行磷酸化等翻译后修饰发挥作用。这一效应受到线粒体结合内质网膜（MAM结构域）的调控，Sigma-1R等MAM蛋白参与了压力超负荷诱导的线粒体动力学失衡过程。内质网应激及自噬也参与了对线粒体分裂融合的调控，通过相应的通路影响线粒体动力学，进而引起心肌细胞肥大。.本课题在动物和细胞水平阐述了线粒体动力学在压力超负荷所致心肌细胞肥大的机制，并且研究了过表达Mfn2、VDAC1等蛋白改善心肌肥厚的机制，在心血管力学生物学和临床医学应用中具有重要意义，可能成为心血管疾病防治的新策略和潜在靶点。在本课题的资助下，申请人已经发表SCI论文11篇，其中 10篇为通讯作者。培养毕业研究生5名。参加学术会议超过5次。