Integrated analysis of m6A mRNA methylation in rats with monocrotaline-induced pulmonary arterial hypertension

Abstract

Background: N6-methyladenosine (m 6 A) modification is one of the most common chemical modifications of eukaryotic mRNAs, which play an important role in tumors and cardiovascular disease through regulating mRNA stability, splicing and translation. However, the changes of m 6 A mRNA and m 6 A-related enzymes in pulmonary arterial hypertension (PAH) remain largely unexplored. Methods: MeRIP-seq was used to identify m 6 A methylation in lung tissues from control and MCT-PAH rats. Western blot and immunofluorescence were used to evaluate expression of m 6 A-related enzymes. Results: Compared with control group, m 6 A methylation was mainly increased in lung tissues from MCT-PAH rats. The up-methylated coding genes in MCT-PAH rats were primarily enriched in processes associated with inflammation, glycolysis, ECM-receptor interaction and PDGF signal pathway, while genes with down-methylation were enriched in processes associated with TGF-β family receptor members. The expression of FTO and ALKBH5 downregulated, METTL3 and YTHDF1 increased and other methylation modification-related proteins was not significantly changed in MCT-PAH rats lung tissues. Immunofluorescence indicated that expression of FTO decreased and YTHDF1 increased in small pulmonary arteries of MCT-PAH rats. Conclusion: m 6 A levels and the expression of methylation-related enzymes were altered in PAH rats, in which FTO and YTHDF1 may play a crucial role in m 6 A modification.

Relevance of RNA N6-Methyladenosine Regulators for Pulmonary Fibrosis: Implications for Chronic Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis

“…Accordingly, YT521-B homology (YTH) domain family is the main “readers” ( Jones et al, 2022 ) and “erasers” consisting of FTO and ALKBH5 ( Kaur et al, 2022 ). Recent studies have focused on the importance of m6A modification in tumors ( Jiang et al, 2022 ; Ma et al, 2022 ; Xiong et al, 2022 ; Yadav et al, 2022 ) and non-neoplastic diseases like asthma and pulmonary hypertension ( Teng et al, 2021 ; Zeng et al, 2021 ; Zhou et al, 2021 ). Nevertheless, the expression pattern of m6A regulators in CHP and IPF remains unclear.…”

Emerging roles of the RNA modifications N6-methyladenosine and adenosine-to-inosine in cardiovascular diseases

“… 78 , 80 No changes were observed in the expression of the majority of other m 6 A regulators, including METTL14, VIRMA, RBM15, YTHDF2-3, YTHDC1-2, or IGF2BP1-3. 78 Contrary to the above findings, lung tissue of rat pups with hypoxic pulmonary hypertension showed downregulated levels of m 6 A residues in RNAs, and decreased expression of METTL3, METTL14, FTO, and ALKBH5. 77 …”

“…Figure 2 offers an overall summary of studies that have assessed either m 6 A or A-to-I RNA modifications in cardiovascular development, physiology, or disease. 50 , 54 , 55 , 56 , 57 , 58 , 54 , 55 , 56 , 57 , 58 , 68 , 67 , 66 , 65 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , …”

m6A Methylation in Cardiovascular Diseases: From Mechanisms to Therapeutic Potential

“…Several studies have reported that m6A methylation levels are significantly upregulated in a rat model of pulmonary hypertension, and these differentially m6A methylated genes proved to be involved in inflammation, glycolysis, endothelial cell receptor activation, and lung development, which can accelerate the progress of pulmonary hypertension ( Xu et al, 2021 ; Zeng et al, 2021 ). Down-regulation of m6A modification by knockdown of METTL3 and METTL14 can delay the progression of pulmonary hypertension by inhibiting the proliferation and migration of pulmonary arterial smooth muscle cells ( Zhou X.-L. et al, 2021 ; Table 3 and Figure 2 ).…”