Table 3. Summary of the main evidence of the involvement of m6A regulators in the pathophysiological process of heart failure.
| Patho-physiology process of HF | Evidence of m6A participating in HF progression | Reference |
|---|---|---|
| Myocardium fibrosis | Interstitial fibrosis result in reduction in myocardium compliance involving various types of molecular, cellular, and interstitial changes | (55-61) |
| Overexpression of FTO improve cardiac function by reducing the collagen deposition | ||
| Over-expression of METTL3 increase the activation of SMAD2/3/TGF-β pathway leading to the accumulation of collagen | ||
| Ventricular hypertrophy | Ventricular hypertrophy is a temporary compensatory mechanism for the increasing after load, which is manifested by ventricular wall thickness, decreases in volume of the ventricular lumen and increase in left ventricular mass | (15,62-65) |
| Hypertrophic failing hearts witnessed higher level of m6A modification verified by m6A sequencing. The failing hearts have overlapped m6A modified transcripts with those hypertrophy heart tissue, which were related to the regulation of gene expression | ||
| METTL3 overexpression in in vivo and in vitro experiments resulted in the lengthening and widening of cardiac cells | ||
| YTHDF2 can degrade the PARP10 transcript. The PARP10 showed elevation in the failing myocardium and knocking down of PARP10 leads to fewer morphological changes related to ventricular hypertrophy and reduced heart mass | ||
| Cardiac cell apoptosis | METTL3 showed correlation with the autophagy process, since METTL3 knockout led to the elevated the LC3II/LC3I ratio suggesting that elevated autophagy flux was occurred, while cell apoptosis was often associated with inhibition of autophagy | (66-74) |
| m6A eraser FTO were shown to increase MHRT expression and reduce myosin heavy chain-associated RNA transcripts in hypoxia-treated cardiomyocytes. MHRT can inhibit apoptosis of myocardial cells | ||
| m6A modification is related to chromosomal modifications. FTO can mediate the demethylation of GADD45B mRNA and increase the stability of the GADD45B transcript, which is an activator of the p38 MAPK pathway mediating reduction of the area of myocardial infarction | ||
| Ischemic reperfusion injury | The myocardium undergone ischemic reperfusion injury showed elevated level of m6A modification both in cell-line and in vivo studies | (75,76,78-80) |
| METTL3 increase the m6A methylation level in the TFEB mRNA and subsequently decrease autophagy flux and lysosomal biogenesis in hypoxia/reoxygenation-treated cardiomyocytes | ||
| METTL14 protect cardiomyocytes from I/R via the activation of Wnt/β-Catenin signaling pathway in m6A dependent manner | ||
| WTAP suppressed H/R-induced cell apoptosis and ER stress in AC16 cells by increasing the m6A level of ATF4 transcription script | ||
| FTO molecule can protect the cardiomyocyte via increasing YAP mRNA stability, which is related to the proliferation and oncogenic activity |
m6A, N6-adenosine methylation; HF, heart failure; FTO, fat mass and obesity-associated gene; METTL3, methyltransferase-like 3; SMAD2/3, Sma and mad related protein 2/3; TGF-β, transforming growth factor β; YTHDF2, YTH domain family 2; LC3, light chain 3; MHRT, myosin heavy chain associated RNA transcript; GADD45B, growth arrest and DNA damage inducible beta; TFEB, transcription factor EB; METTL14, methyltransferase-like 14; I/R, infarction/reperfusion; WTAP, Wilms tumor 1-associating protein; H/R, hypoxia/reperfusion; ER, endoplasmic reticulum; YAP, Yes-associated protein.