Abstract 13959: Role of METTL3 in Regulating Pulmonary Hypertension via Controlling GLUT4 mRNA Translation

Abstract

Introduction: N6-methyladenosine (m6A) modification is one of the most prevalent internal modifications of eukaryotic mRNAs, which plays a crucial role in cardiovascular disease via regulating mRNA splicing, stability, and translation. However, the potential role of m6A modification and its regulatory proteins in pulmonary hypertension (PH) remain largely unexplored. Hypothesis: To investigate the role of m6A modification and its regulatory proteins in the pathogenesis of PH. Methods: m6A level and its regulatory proteins were measured in PH rat models after monocrotaline administration or hypoxia-induced. The global mRNA m6A level was measured by an m6A-RNA methylation quantification kit in lung tissues from PH rats. Western blot was used for m6A regulatory proteins expression analysis. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was performed to analyze the target genes of m6A master regulator METTL3. Pulmonary artery smooth muscle cells (PASMCs) were used for function analysis. Results: m6A level and its regulatory proteins expression including METTL3 were increased in lung tissues from PH rats. m6A RNA immunoprecipitation analysis revealed that GLUT4 as an m6A-regulated gene in PH. Functionally, knockdown of METTL3 reduced expression of GLUT4 and PASMC proliferation. Conclusions: METTL3 promotes PASMC proliferation and PH via enhancing GLUT4 translation in an m6A-dependent manner. This study identified a novel RNA epigenetic mechanism that enhances PASMC proliferation, vascular remodeling, and PH. Thus, m6A modification and its regulatory proteins represent promising therapeutic targets for PH.