YTHDF1 Regulates Pulmonary Hypertension through Translational Control of MAGED1.

Posttranscriptional modifications are implicated in vascular remodeling of pulmonary hypertension (PH). mA (N-methyladenosine) is an abundant RNA modification that is involved in various biological processes. Whether mA RNA modification and mA effector proteins play a role in pulmonary vascular remodeling and PH has not been demonstrated. To determine whether mA modification and mA effectors contribute to the pathogenesis of PH. mA modification and YTHDF1 expression were measured in human and experimental PH samples. RNA immunoprecipitation analysis and mA sequencing were employed to screen mA-marked transcripts. Genetic approaches were employed to assess the respective roles of and in PH. Primary cell isolation and cultivation were used for function analysis of pulmonary artery smooth muscle cells (PASMCs). Elevated mA levels and increased YTHDF1 protein expression were found in human and rodent PH samples as well as in hypoxic PASMCs. The deletion of ameliorated PASMC proliferation, phenotype switch, and PH development both and . mA RNA immunoprecipitation analysis identified as an mA-regulated gene in PH, and genetic ablation of MAGED1 improved vascular remodeling and hemodynamic parameters in SU5416/hypoxia mice. YTHDF1 recognized and promoted translation of in an mA-dependent manner that was absent in -deficient PASMCs. In addition, silencing inhibited hypoxia-induced proliferation of PASMCs through downregulating PCNA. YTHDF1 promotes PASMC proliferation and PH by enhancing MAGED1 translation. This study identifies the mA RNA modification as a novel mediator of pathological changes in PASMCs and PH.