Abstract 321: Miat Long Non-coding Rna Regulates Cardiac Hypertrophy and Ribosomal Expression in Cardiomyocytes

Abstract

Cardiac hypertrophy is characterized by elevated protein synthesis and pathological cardiomyocyte enlargement. The mechanisms underlying the stress response in ribosomal remodeling at organelle level during cardiac hypertrophy is not fully established. We have identified a long non-coding RNA, Myocardial Infarction Associated Transcript (MIAT), that is significantly associated with pathological cardiac hypertrophy through a systems genetic analysis. MIAT expression is induced by hypertrophic signal, and silencing of the MIAT gene significantly blocks myocyte hypertrophy in response to hypertrophic stimuli associated with diminished global protein synthesis activities. Furthermore, MIAT inactivation significantly reduces ribosomal genes at mRNA and protein levels, and reduces protein synthesis activity at basal and post-hypertrophic stimulation in vitro and in vivo . Using a MIAT knockout mouse model, we investigated the in vivo pathophysiological impact of MIAT in pressure-overload induced cardiac hypertrophy and heart failure. Remarkably, we find that the MIAT knockout mice show significantly blunted cardiac hypertrophy and preserved cardiac function following pressure-overload. This study highlights a novel mechanism of translational regulation by a lncRNA MIAT. The outcome will expand functional role of lncRNAs in heart diseases and advance our current understanding of the complexity of regulatory circuits in cardiac hypertrophy and heart failure. It will provide novel insights to protein synthesis and ribosomal regulation and reveal potential therapeutic targets for pathological hypertrophy.