mA Modification-mediated GRAP Regulates Vascular Remodeling in Hypoxic Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling induced by human pulmonary arterial smooth muscle cell (HPASMC) proliferation, migration, and apoptosis resistance. mA (-methyladenosine) is the most prevalent RNA posttranscriptional modification in eukaryotic cells. However, its role in PAH remains elusive. We designed this study to investigate whether mA modification and its effector proteins play a role in pulmonary vascular resistance. Lung samples were used to profile mA concentrations in control subjects and patients with PAH. Bioinformatics analysis, real-time PCR, immunohistochemistry, and Western blotting were used to determine the role of mA effectors in PAH. The biological effects of modified by mA were investigated using and models. Furthermore, RIP-PCR was used to assess the writers and readers of . In this study, we revealed that mA-modified mRNA was upregulated in PAH lung samples, cHx/Su-induced mouse models, and hypoxia-stimulated HPASMCs; however, mRNA and protein were abnormally downregulated. Functionally, overexpression of GRAP drastically alleviated the proliferative and invasive ability of PAH HPASMCs through inhibition of the Ras/ERK signaling pathway and . In addition, METTL14 (methyltransferase-like 14) and the mA binding protein YTHDF2 were significantly increased in PAH. Moreover, we found that mA-modified mRNA was recognized by YTHDF2 to mediate the degradation. expression was consistently negatively correlated with METTL14 and YTHDF2 and . Taken together, for the first time, our findings highlight the function and therapeutic target value of GRAP and extend our understanding of the importance of RNA epigenetics in PAH.