lnc-RPP30-2/Fis1介导的线粒体自噬在心肌纤维化进展中的作用及机制研究

心肌纤维化是结构性心脏病晚期心室重构的常见病理性标记，与心律失常、心力衰竭等的发生密切相关。心肌纤维化患者病情进展缓急程度差异极大，其调控机制尚未完全阐明，亦无针对性的治疗措施和有效的疾病进展预测手段。长链非编码RNAs被报道可能参与调节心肌纤维化，但其具体作用机制尚待进一步研究。线粒体自噬是选择性清除受损和老化线粒体的有效调控机制，目前尚无研究直接阐明线粒体自噬在心肌纤维化中的作用。本项目首次在肥厚型心肌病患者心脏组织标本中筛选出与心肌纤维化程度密切相关的lnc-RPP30-2，初步研究揭示其作用靶标为线粒体分裂蛋白Fis1，并首次提出Fis1可能通过线粒体自噬途径互作激活PI3K/Akt，改变心肌成纤维细胞活性氧及能量代谢，从而调控心脏成纤维细胞向肌成纤维细胞的分化并参与调控心肌纤维化。研究结果将有助于进一步阐明心肌纤维化的发病机制，提供新的心肌纤维化潜在治疗靶点和疾病进展预测标记物。

Cardiac fibrosis is a histopathologic hallmark of a variety of advanced heart diseases, and is closely associated with arrhythmias and heart failure. The degree of disease progression varies greatly among patients with cardiac fibrosis, the regulatory mechanism has not been fully elucidated, and there are no targeted regimen and effective mean for progression prediction. Long non-coding RNAs have been reported to be involved in the occurrence and development of cardiac fibrosis, but future studies are needed to clarify the specific mechanism. Mitophagy is an effective regulatory mechanism for selective clearance of damaged and aging mitochondria. As noted, no studies to date have directly assessed the impact of mitophagy in cardiac fibrosis. Our preliminary studies revealed, for the first time, that lnc-RPP30-2 is closely related to the degree of cardiac fibrosis in patients with hypertrophic cardiomyopathy through chip screening and qPCR experiments in myocardial tissues, and mitochondrial fission protein 1 (Fis1) may be the target of lnc-RPP30-2. Moreover, we put forward for the first time that Fis1, which is generally regarded involved in the mitochondrial fission, may alter the reactive oxygen species and energy metabolism of cardiac fibroblasts, regulate the differentiation of cardiac fibroblasts to myofibroblasts, and participate in the regulation of cardiac fibrosis via mediating mitophagy and interacting with PI3K/AKT activation. This study will help to further elucidate the pathogenesis of cardiac fibrosis, and shed light on potential therapeutic targets and predictive markers for disease progression.