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

项目摘要： 心力衰竭（HF）是由心肌细胞（CM）肥大和凋亡引起的， 心脏成纤维细胞（CF）增殖和纤维化;这些是心脏病理学的标志。 重塑，这是伴随着特定的miRNA表达的变化， MEG基因（MEG）。早期心脏肥大（CH）诱导代偿性 线粒体蛋白质翻译终点HF伴有线粒体蛋白减少 合成和功能失调的线粒体。一般认为，恢复线粒体蛋白 表达和功能减轻了HF进展，突出了阐明基因的重要性。 线粒体中的调节机制，以指导改进的HF治疗剂的开发。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MEG。然而，MEG mRNA的调节机制 心脏中NEMG mRNA的翻译及其与NEMG mRNA翻译的协调仍然几乎未被探索。 我们已经确定了一个miR-574-Fam 210 a轴，该轴维持MEG的最佳翻译， CM和CF中的线粒体稳态，作为一种代偿性心脏保护途径， 与大多数其他单链miRNAs相比，miR-574产生2个功能性的 链，miR-574- 5 p和miR-574- 3 p。在CH早期，miR-574- 5 p拮抗Fam 210 a 在CM中表达以防止MEG过度表达，增强ROS产生和受损 线粒体活性，从而防止CM肥大和凋亡。此外，肥大 应激激活Src激酶介导Tyr 359磷酸化和hnRNP的细胞质积累 以CM为单位的L。P-hnRNP L捕获miR-574- 3 p并促进外泌体介导的miR-574- 3 p释放 并通过靶向CF Fam 210 a来减少心脏成纤维细胞（CF）增殖。我们的中心假设是： 在CM和CF中，miR-574-Fam 210 a轴维持了miR-574编码基因的最佳翻译 和线粒体稳态，从而限制病理性心脏肥大和心室 重塑我们将通过追求三个目标来检验这个假设。目标1.阐明了导卫机构 链miR-574- 5 p在预防病理性心肌肥大和CM凋亡中的作用。目标2.建立 miR-574- 3 p在抗心肌纤维化中的作用及其机制目标3. 确定Fam 210 a在线粒体翻译调控中的功能和机制， 调节心脏功能。

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.