Mettl14 Attenuates Cardiac Ischemia/Reperfusion Injury by Regulating Wnt1/β-Catenin Signaling Pathway

Abstract

N6-methyladenosine (m6A) methylation in RNA is a dynamic and reversible modification regulated by methyltransferases and demethylases, which has been reported to participate in many pathological processes of various diseases, including cardiac disorders. This study was designed to investigate an m6A writer Mettl14 on cardiac ischemia–reperfusion (I/R) injury and uncover the underlying mechanism. The m6A and Mettl14 protein levels were increased in I/R hearts and neonatal mouse cardiomyocytes upon oxidative stress. Mettl14 knockout (Mettl14+/−) mice showed pronounced increases in cardiac infarct size and LDH release and aggravation in cardiac dysfunction post-I/R. Conversely, adenovirus-mediated overexpression of Mettl14 markedly reduced infarct size and apoptosis and improved cardiac function during I/R injury. Silencing of Mettl14 alone significantly caused a decrease in cell viability and an increase in LDH release and further exacerbated these effects in the presence of H2O2, while overexpression of Mettl14 ameliorated cardiomyocyte injury in vitro. Mettl14 resulted in enhanced levels of Wnt1 m6A modification and Wnt1 protein but not its transcript level. Furthermore, Mettl14 overexpression blocked I/R-induced downregulation of Wnt1 and β-catenin proteins, whereas Mettl14+/− hearts exhibited the opposite results. Knockdown of Wnt1 abrogated Mettl14-mediated upregulation of β-catenin and protection against injury upon H2O2. Our study demonstrates that Mettl14 attenuates cardiac I/R injury by activating Wnt/β-catenin in an m6A-dependent manner, providing a novel therapeutic target for ischemic heart disease.

Downregulated ALKBH5 contributes to myocardial ischemia/reperfusion injury by increasing m6A modification of Trio mRNA

“…Multiple studies have shown that the latent regulatory mechanisms of m 6 A modification are associated with a variety of cardiovascular disease (18,19). It has been reported that the m6A and METTL14 protein levels are increased in MIRI hearts and neonatal mouse cardiomyocytes upon oxidative stress (38). Increased FTO could block apoptosis of myocardial cells with hypoxia/reoxygenation through changing m 6 A modification of Mhrt (39); WTAP could facilitate MIRI via regulating m 6 A modification of activating transcription factor 4 (ATF4) (40); and METTL3 could weaken apoptosis of cardiomyocyte with MIRI (41).…”

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

“…136 Interestingly, in global Mettl114 +/À mice with worsened I/R-injury phenotype compared with controls, WTAP was identified as the only differentially expressed, i.e., upregulated, m 6 A writer subunit. 143 Finally, based on bioinformatic reanalysis of up to 108 ischemic, 16 nonischemic, and 86 idiopathic human myocardium specimens, WTAP was also identified as the most consistently upregulated of the m 6 A governing enzymes. 133 Hence, WTAP might be unveiled as a biomarker in human ischemic cardiac pathologies.…”

“… 120 Mettl14 +/− mice have also demonstrated with normal cardiac structure and function at 10 weeks of age. 143 Nonetheless, some focused m 6 A activity appears indispensable for postnatal cardiac development as heart-specific conditional knockout YTHDC1 m 6 A reader protein has been described to result in premature death of mice at 2–3 months of age due to disrupted m 6 A-dependent splicing of Titin pre-mRNA, accompanied by destructed sarcomere organization, DCM, and ultimately HF. 150 On the other hand, cardiogenesis and postnatal development seem to proceed normally in knockout mice lacking YTHDF1, 150 , 187 YTHDF2, 188 YTHDF3, 150 ALKBH5, 54 , 189 or either global 119 or cardiomyocyte-targeted FTO knockout.…”

“… 142 However, myocardial METTL3 overexpression has also been implicated with cardioprotective ability by (1) inducing therapeutic myocardial angiogenesis in mice shortly after MI, 56 (2) lessening post-MI damage in rats by promoting cardiomyocyte proliferation via stimulated pri-miR-17-3p maturation, 147 and (3) its non-catalytic METTL14 subunit protecting mice heart from extensive I/R injury by activating Wnt1/β-catenin signal pathway via an m 6 A-dependent enhanced Wnt family member 1 ( Wnt1 ) mRNA translation. 143 Hence, it can be postulated that the resulting final effect on the cardiac phenotype depends considerably on the relative weights of METTL3 activity within the distinct cardiac cell types, ischemic models, as well as the expression profile of the m 6 A readers and transcribed transcriptome available for methylation at a given time, as discussed above (see section “ cardiac hypertrophy and failure ”).…”

The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer

“…Recent researches have demonstrated that dysregulation of METTL14 is tightly relative to the phenotypes involved in the malignant development of various cancer, including proliferation [88][89][90], metastasis [91][92][93][94][95][96], apoptosis [97][98][99][100][101], drug resistance [102][103][104][105], cancer stem cell like characteristic [106,107], immunotherapy [21,108,109], chronic inflammation [110] and glycolipid metabolism (Fig. 2) [95].…”