Inhibition of YTHDF1 prevents hypoxia-induced pulmonary artery smooth muscle cell proliferation by regulating Foxm1 translation in an m6A-dependent manner

Feb 3, 2023Experimental cell research

Blocking YTHDF1 may stop low-oxygen-driven growth of lung artery muscle cells by controlling Foxm1 protein production through m6A modification

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Abstract

YTHDF1 silencing reduced hypoxic pulmonary artery smooth muscle cell (PASMC) proliferation by inhibiting the translation of Foxm1.

Hypoxia is identified as a significant risk factor for the progression of pulmonary arterial hypertension (PAH).
Silencing YTHDF1 led to a greater reduction in hypoxic PASMC proliferation and Foxm1 protein levels compared to silencing YTHDF2 or YTHDF3.
YTHDF1 enhances the translation efficiency of Foxm1 mRNA in a process dependent on a specific chemical modification (m6A).
In mice, silencing YTHDF1 alleviated pulmonary vascular changes, reduced right ventricular systolic pressure (RVSP), and inhibited proliferation marker levels.
The study suggests a potential mechanism where YTHDF1 regulates hypoxic PASMC proliferation through its interaction with Foxm1.

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Pulmonary arterial hypertension (PAH) is a chronic disease characterized by pulmonary vascular remodeling. It refers to the abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs), and hypoxia is an important risk factor for this progression. The present study aims to investigate the role of YTHDF1 in the regulation of hypoxic PASMC proliferation and the underlying mechanism. Human PASMCs were transfected with si-YTHDF1/2/3 followed by treatment of hypoxia, and the PASMC proliferation and Foxm1 expression were detected. Through RNA pull-down, RNA immunoprecipitation, and protein synthesis assay, the mechanism of YTHDF1 regulating Foxm1 was explored. Next, Foxm1 was inhibited by thiostrepton, and cell proliferation was detected. In vivo, mice received a tail vein injection of adenovirus containing si-YTHDF1 and were exposed to hypoxia treatment. Pulmonary vascular changes, right ventricular systolic pressure (RVSP), and genes involving proliferation were analyzed. YTHDF1 silencing reduced more hypoxic PASMC proliferation and Foxm1 protein level than YTHDF2/3 silencing. Mechanical results showed that YTHDF1 interacted with Foxm1 mRNA and up-regulated Foxm1 protein level by enhancing the translation efficiency in an m6A-dependent manner. Furthermore, YTHDF1 facilitated hypoxic PASMC proliferation and proliferation marker expressions through up-regulation of Foxm1 in an m6A-dependent manner. In vivo, the YTHDF1 silencing alleviated pulmonary vascular changes and fibrosis, reduced RVSP, inhibited the interaction of YTHDF1 and Foxm1, and reduced proliferation marker levels, as compared to the PAH group. In conclusion, YTHDF1 silencing inhibits hypoxic PASMC proliferation by regulating Foxm1 translation in an m6A-dependent manner.

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Inhibition of YTHDF1 prevents hypoxia-induced pulmonary artery smooth muscle cell proliferation by regulating Foxm1 translation in an m6A-dependent manner

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