铁自噬促SFXN1依赖性线粒体铁超载介导apelin-13促心肌细胞肥大

The applicant has reported that autophagy can mediate cardiomyocyte hypertrophy induced by APJ receptors and its endogeneous ligand-apelin-13.Besides, related articles have found that iron overload can induce oxidative damage increasing, stimulating cardiomyocyte hypertrophy. Preliminary experiments have also found that apelin-13 increases the expression of the maker protein of ferritinophagy-NCOA4 and the mitochondrial membrane transporter SFXN1 in H9c2 cardiomyocytes as well as the contents of free iron and reactive oxygen species in mitochondria. According to that, the scientific hypothesis “by activating APJ receptor, apelin-13 induces the occurrence of ferritinophagy and promotes SFXN1-dependent mitochondrial iron overload, causing cardiomyocyte hypertrophy”can be proposed. Applicant will adopt RNAi and other methods to clarify whether apelin-13 could promote ferritinophagy in myocardial cells；To illustrate whether apelin-13 induces SFXN1-dependent mitochondrial iron overload, whether ferritinophagy regulates apelin-13-induced SFXN1-dependent mitochondrial iron overload; To analyze whether ferritinophagy promoting SFXN1-dependent mitochondrial iron overload mediates cardiomyocyte hypertrophy induced by apelin-13. From the new perspective of ferritinophagy and SFXN1-dependent mitochondrial iron overload,this research reveales a new mechanism of apelin/APJ system to promote cardiomyocyte hypertrophy and provides experimental basis for APJ receptor as a new target for cardiac hypertrophy treatment.

申请者前期报道自噬介导APJ受体及其内源性配体apelin-13促心肌细胞肥大，文献报道铁超载诱导氧化损伤增加，刺激心肌细胞肥大；预实验发现apelin-13促H9c2心肌细胞铁自噬标志蛋白NCOA4和线粒体膜转运蛋白SFXN1表达，增加线粒体内游离铁和活性氧含量，据此提出“铁自噬促SFXN1依赖性线粒体铁超载介导apelin-13促心肌细胞肥大”科学假说。课题拟采用RNA干扰等方法明确apelin-13是否诱导心肌细胞铁自噬；分析apelin-13是否促进SFXN1依赖性线粒体铁超载，铁自噬是否调控apelin-13诱导的SFXN1依赖性线粒体铁超载；探讨铁自噬促SFXN1依赖性线粒体铁超载是否介导apelin-13促心肌细胞肥大。课题从铁自噬、SFXN1依赖性线粒体铁超载视角揭示apelin/APJ促心肌细胞肥大新机理，为APJ受体成为心肌肥厚治疗新靶点提供实验依据。

Apelin是G蛋白偶联受体APJ的内源性配体，在心血管系统形成及相关疾病的发生发展中具有重要作用。本实验室前期研究结果发现，apelin-13具有诱导心肌细胞肥大的作用，且自噬途径参与了apelin-13诱导的心肌细胞肥大过程。铁自噬(Ferritinophagy)是最新发现的一种调节细胞内铁代谢的选择性自噬。过度激活铁自噬可能诱导细胞内铁超载从而参与心肌肥厚的发展。本课题拟研究apelin-13对铁自噬及线粒体铁代谢的影响，并在前期研究的基础上探讨铁自噬-线粒体铁离子转运蛋白Sideroflexin1 (SFXN1) 依赖性线粒体铁超载介导apelin-13促心肌细胞肥大的新机制，揭示apelin-13/APJ系统诱导心肌肥厚的新的作用机制，为开发以APJ为靶点的抗心肌肥厚药物提供新的实验依据