Role of miR-574-Fam210a axis in cardiac hypertrophy and remodeling

项目总结： 心力衰竭(HF)是由心肌细胞(CM)肥大和凋亡引起的，与 心脏成纤维细胞(CF)增殖和纤维化；这些是心脏病理的特征 重塑，伴随着特定miRNAs和 线粒体编码基因(MEGS)。早期心肌肥厚(CH)引起的代偿 线粒体蛋白翻译。终点心衰伴随线粒体蛋白减少 线粒体的合成和功能失调。人们普遍认为，恢复线粒体蛋白 表达和功能减缓心力衰竭的进展，强调澄清基因的重要性 线粒体中的调节机制，以指导改进的HF疗法的开发。许多 研究已经检查了协调核编码的mRNA转录的机制。 线粒体基因(NEMG)和MEGS。然而，MEG mRNA的调控机制 翻译及其与心脏内NEMG mRNA翻译的协调几乎仍未被探索。 我们已经确定了一个miR-574-Fam210a轴，它维持MEGS和Megs的最佳翻译 CM和CF中线粒体稳态作为一种代偿性心肌保护途径 华夏早期。与大多数其他单链miRNAs相比，miR-574产生2个功能 链，miR-574-5P和miR-574-3P。在慢性阻塞性肺疾病早期，miR-574-5P拮抗Fam210a 在CM中表达可防止MEG过度表达，增加ROS的产生和受损 线粒体活性增强，从而防止心肌肥大和细胞凋亡。此外，肥厚性 应激激活Src激酶介导的Tyr359磷酸化和hnRNP的胞内积聚 L在CM。P-hnRNP L捕获miR-574-3p并促进外体介导的miR-574-3p的释放 并通过靶向心脏成纤维细胞(CFFam210a)抑制CFs的增殖。我们的中心假设是： 在CM和CF中，miR-574-Fam210a轴维持线粒体编码基因的最佳翻译 和线粒体动态平衡，从而限制病理性心肌肥厚和心室 改建。我们将通过追求三个目标来检验这一假设。目的1.阐明GUIDE的作用机制 MiR-574-5p链对病理性心肌肥厚和心肌细胞凋亡的保护作用目标2.建立 客体链miR-574-3p抗心肌纤维化的作用及机制目标3. 确定Fam210a在线粒体翻译调控中的功能和机制 心功能的调节。

Project Summary: Heart Failure (HF) results from cardiomyocyte (CM) hypertrophy and apoptosis, combined with cardiac fibroblast (CF) proliferation and fibrosis; these are hallmarks of cardiac pathological remodelling, which is accompanied by changes in the expression of specific miRNAs and mitochondrial-encoded genes (MEGs). Early stage cardiac hypertrophy (CH) induces compensatory mitochondrial protein translation. Endpoint HF is accompanied by reduced mitochondrial protein synthesis and dysfunctional mitochondria. It is generally accepted that restoring mitochondrial protein expression and function mitigates HF progression, highlighting the importance of clarifying gene regulation mechanisms in mitochondria to guide development of improved HF therapeutics. Many studies have examined mechanisms that coordinate mRNA transcription of nuclear-encoded mitochondrial genes (NEMGs) and MEGs. However, regulatory mechanisms of MEG mRNA translation and its coordination with NEMG mRNA translation in the heart remain virtually unexplored. We have identified a miR-574-Fam210a axis that maintains the optimal translation of MEGs and mitochondrial homeostasis in both CM and CF, as a compensatory cardioprotective pathway at an early stage of CH. In contrast to most other single strand miRNAs, miR-574 produces 2 functional strands, miR-574-5p and miR-574-3p. At early stage of CH, miR-574-5p antagonizes Fam210a expression in CM to prevent excessive MEG expression, enhanced ROS production and impaired mitochondrial activity, thereby preventing CM hypertrophy and apoptosis. Moreover, hypertrophic stress activates Src kinase-mediated Tyr359 phosphorylation and cytoplasmic accumulation of hnRNP L in CM. P-hnRNP L captures miR-574-3p and promotes exosome-mediated release of miR-574-3p and reduces cardiac fibroblasts (CF) proliferation by targeting CF Fam210a. Our central hypothesis is: in CM and CF, miR-574-Fam210a axis maintains optimal translation of mitochondrial-encoded genes and mitochondrial homeostasis, thereby limiting pathological cardiac hypertrophy and ventricular remodeling. We will test this hypothesis by pursuing 3 aims. Aim 1. Elucidate the mechanism of guide strand miR-574-5p in preventing pathological cardiac hypertrophy and CM apoptosis. Aim 2. Establish the role and mechanism of passenger strand miR-574-3p in antagonizing cardiac fibrosis. Aim 3. Determine the function and mechanism of Fam210a in mitochondrial translational control and regulation of cardiac function.