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

Area of Science:

• Molecular Biology
• Cardiovascular Research
• Epigenetics

Background:

• N6-methyladenosine (m⁶A) RNA modification and its regulators are implicated in pulmonary hypertension (PH) pathogenesis.
• Ythdf2 (YTH N6-methyladenosine RNA binding protein 2) degrades m⁶A-modified mRNAs and is linked to PH and pulmonary artery smooth muscle cell (PASMC) proliferation.
• The specific roles of Ythdf2 in PASMCs and its downstream targets in PH development require clarification.

Purpose of the Study:

• To investigate the expression and function of Ythdf2 in PASMCs during PH.
• To identify downstream targets of Ythdf2 in PASMCs in the context of PH.
• To elucidate the molecular mechanisms by which Ythdf2 contributes to PH.

Main Methods:

• Investigated Ythdf2 expression and function in human and rodent PH-PASMCs.
• Utilized smooth muscle cell-specific Ythdf2-deficient mice for in vivo studies.
• Employed proteomic analysis, m⁶A sequencing, and RNA immunoprecipitation to identify downstream targets.

Main Results:

• Ythdf2 was upregulated in PH-PASMCs; its deficiency ameliorated PH development and PASMC proliferation.
• Ythdf2 stabilized Myadm mRNA in an m⁶A-dependent manner, promoting PASMC proliferation and PH.
• Loss of Ythdf2 decreased Myadm expression, and silencing Myadm inhibited Ythdf2-dependent PASMC hyperproliferation via p21 upregulation.

Conclusions:

• Identified a novel m⁶A/Myadm/p21 pathway where increased Ythdf2 drives PH-PASMC proliferation.
• Ythdf2 targeting in PASMCs presents a potential therapeutic strategy for pulmonary hypertension.