High levels of m6A methylation of Grb-2-related adaptor protein (GRAP) mRNA are related to pulmonary artery remodeling in pulmonary arterial hypertension (PAH), a new study published in the American Journal of Respiratory Cell and Molecular Biology found

The study also reported that reduced GRAP expression accelerates the proliferation and migration of pulmonary arterial smooth muscle cells by activating the Ras/ERK signaling pathway.

Finally, the study showed that the m6A modification of GRAP mRNA driven by methyltransferase-like 14 (METTL14 ) through the m6A reader YTHDF2 accelerates the development of PAH and that YTHDF2 recognizes m6A-modified GRAP mRNA and promotes its degradation.


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“These presented findings not only provide novel insight into the epigenetic regulatory mechanism of PAH but also pave the way for targeting the METTL14/YTHDF2/GRAP axis as a promising and attractive therapeutic strategy for PAH,” the authors of the study wrote. 

Read more about experimental therapies for PAH.

m6A is the most common posttranscriptional RNA modification in eukaryotic cells, but its role in PAH is not well understood.

The aim of the present study was to clarify whether m6A modification and its effector proteins are involved in pulmonary vascular resistance. The researchers assessed m6A levels in lung samples from patients with PAH and controls. They also investigated the biological effects of GRAP modified by m6A.

They found that m6A-modified GRAP mRNA was upregulated in lung samples from PAH patients as well as a mouse model of PAH and human pulmonary arterial smooth muscle cells subjected to hypoxia. Similarly, METTL14 and YTHDF2 were significantly increased in PAH and that YTHDF2 recognized m6A-modified GRAP mRNA.

When they overexpressed GRAP, the researchers found the proliferation and migration of pulmonary arterial smooth muscle cells were dramatically reduced.

“Taken together, for the first time, our findings highlight the function and therapeutic target value of GRAP and extend understanding of the importance of RNA epigenetics in PAH,” the researchers concluded. 

Reference

Liu P, Zhang A, Ding Z, et al. m6A modification-mediated GRAP regulates vascular remodeling in hypoxic pulmonary hypertension. Am J Respir Cell Mol Biol. Published online August 16, 2022. doi:10.1165/rcmb.2021-0429OC