Loss of Lin28a Attenuates Cardiac Hypertrophy Induced by Pressure Overload

Pathological cardiac hypertrophy is a major risk factor for the development of heart failure and sudden cardiac death, yet the molecular mechanism of cardiac hypertrophy is not fully understood. Recently, we found that the expression of Lin28a, a RNA-binding protein, was significantly upregulated during the early stages of cardiac hypertrophy. Interestingly, cardiac specific conditional deletion of Lin28a blunted pressure overload-induced cardiac hypertrophic responses. Given that Lin28a can bind to diverse mRNA to regulate their abundance and/or translation, we conducted RNA-seq to profile the cardiac transcriptome alteration without Lin28a under pressure overload. It showed that metabolic pathways, including glycolysis and biosynthetic pathway, were remarkedly affected. Thus, our study identifies Lin28a as a crucial regulator of cardiac hypertrophy via its role in metabolic programming. Overall design: Cardiac mRNA profiles of cardiac specific Lin28 knockout mice and their control littermates subjected to pressure overload at Day 5 were generated by deep sequencing, in duplicate, using Illumina HiSeq 2500 (50bp x2).病理性心肌肥厚（Pathological cardiac hypertrophy）是心力衰竭与心源性猝死发生的主要危险因素，然而目前心肌肥厚的分子机制尚未完全阐明。近期我们发现，RNA结合蛋白（RNA-binding protein）Lin28a在心肌肥厚早期的表达水平显著上调。有趣的是，心肌特异性条件性敲除Lin28a可削弱压力负荷诱导的心肌肥厚反应。鉴于Lin28a能够结合多种mRNA以调控其丰度和/或翻译过程，我们开展了RNA测序（RNA-seq）以分析压力负荷状态下缺失Lin28a时心脏转录组的变化情况。结果显示，包括糖酵解、生物合成通路在内的代谢通路受到显著影响。因此，本研究证实Lin28a通过调控代谢重编程，成为心肌肥厚的关键调控因子。总体实验设计：采用Illumina HiSeq 2500（50bp×2）平台，对压力负荷造模第5天的心肌特异性Lin28a敲除小鼠及其同窝对照小鼠的心脏mRNA进行深度测序，每个样本设置两个生物学重复。