Smooth Muscle Ythdf2 Abrogation Ameliorates Pulmonary Vascular Remodeling by Regulating Myadm Transcript Stability.

Background: The N6-methyladenosine (mA) modification of RNA and its regulators have important roles in the pathogenesis of pulmonary hypertension (PH). (YTH N6-methyladenosine RNA binding protein 2) is best known for its role in degrading mA-modified mRNAs such as mRNA, which leads to alternative activation of macrophages in PH. Recent studies have also linked to the proliferation of pulmonary artery smooth muscle cells (PASMCs). However, its specific roles in PASMCs and downstream targets during the development of PH remain unclear.

Methods: The expression and biological function of in PASMCs were investigated in human and experimental models of PH. Smooth muscle cell-specific -deficient mice were used to assess the roles of in PASMCs in vivo. Proteomic analysis, mA sequencing, and RNA immunoprecipitation analysis were used to screen for potential downstream targets.

Results: Ythdf2 was significantly upregulated in human and rodent PH-PASMCs, and smooth muscle cell-specific deficiency ameliorated PASMC proliferation, right ventricular hypertrophy, pulmonary vascular remodeling, and PH development. Higher expression of Ythdf2 promoted PASMC proliferation and PH by paradoxically stabilizing mRNA in an mA-dependent manner. Loss of decreased the expression of Myadm in PASMCs and pulmonary arteries, both in vitro and in vivo. Additionally, silencing inhibited the -dependent hyperproliferation of PASMCs by upregulating the cell cycle kinase inhibitor p21.

Conclusions: We have identified a novel mechanism where the increased expression of stimulates PH-PASMC proliferation through an mA/Myadm/p21 pathway. Strategies targeting in PASMCs might be useful additions to the therapeutic approach to PH.