SEDT2/METTL14-mediated m6A methylation awakening contributes to hypoxia-induced pulmonary arterial hypertension in mice

Mar 4, 2021Aging

How SEDT2/METTL14-related m6A methylation may trigger low-oxygen lung artery high blood pressure in mice

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Abstract

Elevated expression of SETD2 and METTL14 is observed in pulmonary artery smooth muscle cells of hypoxia-induced PAH mice.

The lack of SETD2 in smooth muscle cells protects mice from hypoxia-induced pulmonary arterial hypertension.
Significant reductions in right ventricular systolic pressure and heart weight ratios are noted in SETD2 knockout mice.
Absence of SETD2 also lowers METTL14 expression and mA RNA methylation levels in pulmonary artery smooth muscle cells.
These findings suggest that inhibiting SETD2/METTL14 activity may offer potential treatment options for PAH.

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Pulmonary arterial hypertension (PAH) is a fatal disease whose molecular mechanism is unknown. The trimethylation of lysine 36 on histone 3 (H3K36me3) catalyzed by SETD2 and the modification of N6-methyladenine (mA) mRNA mediated by METTL14 play important roles in a variety of normal and pathological biological processes. However, the role of these epigenetic controls in the pathogenesis of PAH remains unclear. In this study, the expression of SETD2 and METTL14 was elevated in pulmonary artery smooth muscle cells (PASMCs) of hypoxia-induced PAH mice. We further constructed a mouse model with SETD2 specific knockout in smooth muscle cells (SETD2). Our results suggest that the lack of SETD2 in SMCs protected mice from hypoxia-induced PAH and significantly reduced right ventricular systolic pressure (RVSP), right ventricular/left ventricular plus septum [RV/(LV+S)] weight ratio, and pulmonary median width. In addition, the absence of SETD2 in SMCs alleviates the level of METTL14 expression and the mA RNA methylation level in PAH SMCs. These results obtained from mice suggest that strategies that target the inhibition of SETD2/METTL14 activity may be a viable treatment for PAH in a clinical setting. 6SM22α Cre6

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SEDT2/METTL14-mediated m6A methylation awakening contributes to hypoxia-induced pulmonary arterial hypertension in mice

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