Alteration of m6A RNA Methylation in Heart Failure With Preserved Ejection Fraction

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease, in which its pathogenesis is very complex and far from defined. Here, we explored the N6-methyladenosine (m6A) RNA methylation alteration in patients with HFpEF and mouse model of HFpEF.Methods: In this case–control study, peripheral blood mononuclear cells (PBMCs) were separated from peripheral blood samples obtained from 16 HFpEF patients and 24 healthy controls. The change of m6A regulators was detected by quantitative real-time PCR (RT-PCR). A “two-hit” mouse model of HFpEF was induced by a high-fat diet and drinking water with 0.5 g/L of Nω-nitro-l-arginine methyl ester (L-NAME). MeRIP-seq was used to map transcriptome-wide m6A in control mice and HFpEF mice, and the gene expression was high-throughput detected by RNA-seq.Results: The expression of m6A writers METTL3, METTL4, and KIAA1429; m6A eraser FTO; and reader YTHDF2 was up-regulated in HFpEF patients, compared with health controls. Furthermore, the expression of FTO was also elevated in HFpEF mice. A total of 661 m6A peaks were significantly changed by MeRIP-seq. Gene Ontology (GO) analysis revealed that protein folding, ubiquitin-dependent ERAD pathway, and positive regulation of RNA polymerase II were the three most significantly altered biological processes in HFpEF. The pathways including proteasome, protein processing in the endoplasmic reticulum, and PI3K-Akt signaling pathway were significantly changed in HFpEF by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.Conclusions: The expression pattern of m6A regulators and m6A landscape is changed in HFpEF. This uncovers a new transcription-independent mechanism of translation regulation. Therefore, our data suggest that the modulation of epitranscriptomic processes, such as m6A methylation, might be an interesting target for therapeutic interventions.

Exploration of Potential Genetic Biomarkers for Heart Failure: A Systematic Review

“…The included studies were published between 2007 and 2021. Twenty-three studies were conducted in China [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]; ten in the United States [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]; five in Iran [ 47 , 48 , 49 , 50 , 51 ]; four in Italy [ 52 , 53 , 54 , 55 ]; three in the Netherlands [ 56 , 57 , 58 ]; three in Germany [ 59 , 60 , 61 ]; two in Taiwan [ 62 , 63 ]; two in Australia [ 64 , 65 ]; and one each in New Zealand [ 66 …”

“…Five of the included studies reported the change of DNA methylation in HF [ 25 , 35 , 60 , 64 , 70 ]. All of them examined the DNA methylation pattern using peripheral blood.…”

“…In the other four studies, various potential epigenetic biomarkers were reported. They include SLC2A1 , MPV17L and PLEC [ 25 ]; METTL3 , METTL4 , KIAA1429 , FTO and YTHDF2 [ 35 ]; HDAC9 [ 64 ]; HEY2 , MSR1 , MYOM3 , COX17 , MMP2 , CTGF , miR-24-1, and miR-155 [ 70 ].…”

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

“…Although the study of RNA modifications, epitranscriptomics remains in its infancy, methodological breakthroughs of the last decade have enabled identification of these modifications with such accuracy that their large-scale screening is rational [ 117 , 118 , 119 , 120 , 121 , 143 ]. Encouragingly, research findings suggest both m 6 A and A-to-I to act as contributors or even potential initiators and drivers for several cardiovascular physiological and pathological processes including cardiogenesis, angiogenesis, hypertension, hypertrophy, atherosclerosis, ischemia, ischemia-reperfusion, fibrosis, HF, congenital heart disease, stroke, aneurysms, as well as cardiac repair and regeneration [ 25 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 51 , 52 , 53 , 54 , 55 , 56 ]. Remarkably, the first indication for coronary atherosclerosis to be reflected in the m 6 A content of mRNAs and long non-coding RNAs of peripheral mononuclear cells with suggested involvement in its pathophysiology has just recently been reported [ 151 ].…”

“…Silencing or overexpression of enzymes controlling m 6 A abundance has revealed the role of m 6 A in driving immune reactivity, proliferation, apoptosis, and many intracellular processes including mRNA splicing, translation, and degradation [ 20 , 26 ], as well as miRNA biogenesis [ 27 ]. Moreover, reports from diverse fields of research [ 28 , 29 , 30 , 31 ], and in an array of cardiovascular pathologies [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ], provide evidence of m 6 A as a master post-transcriptional regulator.…”