BACKGROUND:
The N6-methyladenosine (m
6
A) modification of RNA and its regulators have important roles in the pathogenesis of pulmonary hypertension (PH).
Ythdf2
(YTH N6-methyladenosine RNA binding protein 2) is best known for its role in degrading m
6
A-modified mRNAs such as
Hmox1
mRNA, which leads to alternative activation of macrophages in PH. Recent studies have also linked
Ythdf2
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
Ythdf2
in PASMCs were investigated in human and experimental models of PH. Smooth muscle cell–specific
Ythdf2
-deficient mice were used to assess the roles of
Ythdf2
in PASMCs in vivo. Proteomic analysis, m
6
A 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
Ythdf2
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
Myadm
mRNA in an m
6
A-dependent manner. Loss of
Ythdf2
decreased the expression of Myadm in PASMCs and pulmonary arteries, both in vitro and in vivo. Additionally, silencing
Myadm
inhibited the
Ythdf2
-dependent hyperproliferation of PASMCs by upregulating the cell cycle kinase inhibitor p21.
CONCLUSIONS:
We have identified a novel mechanism where the increased expression of
Ythdf2
stimulates PH-PASMC proliferation through an m
6
A/Myadm/p21 pathway. Strategies targeting
Ythdf2
in PASMCs might be useful additions to the therapeutic approach to PH.