Michelle Yan

Background: Heart failure is a disease that is characterized by the decreased ability of the heart to pump blood; its typical clinical presentation includes difficulty breathing, fatigue, and ankle swelling.^1,2 Heart failure affects 1.9%-2.6% of the population in the US and more than 64 million people worldwide.^1,3  Currently, besides heart transplantation, the main treatment for heart failure is through inhibition of neuroendocrine stimulation, however, the therapeutic efficacy of this approach is limited, and it does not prevent the progression of the disease.⁴  Therefore, exploring the underlying mechanism of heart failure and identifying novel therapeutic targets are needed. m6A methylation is the methylation modification to N6 position of adenosine in RNA and is the most prevalent modification found in mammalian messenger RNA transcripts.^4,5 This methylation process has been shown to influence RNA splicing, translation, transport, and decay. Fat mass and obesity associated protein (FTO) is an important demethylase used in m6A methylation.⁵

Objective: In this review, we explored the role of fat mass and obesity associated protein (FTO) in heart failure.

Search Methods: An online search in PubMed for articles from 2019 to 2024 using key words “FTO” and “Heart Failure” was conducted.

Results: 24% of RNA transcripts in healthy mouse hearts were m6A methylated, compared to 14.6% in healthy human hearts; these m6A-containing RNA transcripts were mostly associated with the coding sequences and the 3′ untranslated region.⁴ Changes in m6A RNA methylation levels were observed in heart failure and heart hypertrophy, and these methylation changes affected protein abundance, independent of mRNA levels.⁴  In HFpEF (heart failure with preserved ejection fraction) mice and patients, expression levels of most m6A regulators, including FTO, were increased.⁶ FTO expression decreased in hypoxic cardiomyocytes and failing hearts; improving expression of FTO attenuated hypoxia-induced cardiomyocyte dysfunction.⁷  In hypoxia/reoxygenation-treated myocardial cells, FTO was shown to decrease the expression of pro-apoptotic molecules and increase the expression of anti-apoptotic molecules, by regulating m6A methylation of Mhrt (a cardiac specific long non-coding RNA).⁸ FTO reduced cardiac dysfunction by regulating glycolysis and glucose uptake in mice with pressure overload-induced heart failure. FTO overexpression alleviated cardiac dysfunction in mice with heart failure, while knockdown of FTO led to the opposite.⁹ Cinnamic acid decreased heart hypertrophy and mitochondrial dysfunction in part through the enhanced expression of FTO; and FTO was required for cinnamic acid to exert its protective functions.¹⁰

Conclusions: Studies have shown that the expression levels of m6A regulators, including FTO, increase in heart failure. FTO plays roles in processes such as metabolic homeostasis and cardiac contraction in heart failure and is found to attenuate cardiomyocyte dysfunctions in multiple ways. Natural products such as cinnamic acid might help with heart failure, and FTO is important for them to exert their protective functions. Therefore, FTO can be used as a potential therapeutic target for treating heart failure.

Works Cited:

1. Savarese G, Becher PM, Lund LH, Seferovic P, Rosano GMC, Coats AJS. Global burden of heart failure: a comprehensive and updated review of epidemiology [published correction appears in Cardiovasc Res. 2023 Jun 13;119(6):1453]. Cardiovasc Res. 2023;118(17):3272-3287. doi:10.1093/cvr/cvac013
2. Lam CSP, Docherty KF, Ho JE, McMurray JJV, Myhre PL, Omland T. Recent successes in heart failure treatment. Nat Med. 2023;29(10):2424-2437. doi:10.1038/s41591-023-02567-2
3. Bozkurt B, Ahmad T, Alexander KM, et al. Heart Failure Epidemiology and Outcomes Statistics: A Report of the Heart Failure Society of America. J Card Fail. 2023;29(10):1412-1451. doi:10.1016/j.cardfail.2023.07.006
4. Berulava T, Buchholz E, Elerdashvili V, et al. Changes in m6A RNA methylation contribute to heart failure progression by modulating translation. Eur J Heart Fail. 2020;22(1):54-66. doi:10.1002/ejhf.1672
5. Yu L, Cai S, Guo X. m6A RNA methylation modification is involved in the disease course of heart failure. Biotechnol Genet Eng Rev. Published online March 21, 2023. doi:10.1080/02648725.2023.2191086
6. Zhang B, Xu Y, Cui X, et al. Alteration of m6A RNA Methylation in Heart Failure With Preserved Ejection Fraction. Front Cardiovasc Med. 2021;8:647806. Published 2021 Mar 5. doi:10.3389/fcvm.2021.647806
7. Mathiyalagan P, Adamiak M, Mayourian J, et al. FTO-Dependent N6-Methyladenosine Regulates Cardiac Function During Remodeling and Repair. Circulation. 2019;139(4):518-532. doi:10.1161/CIRCULATIONAHA.118.033794
8. Shen W, Li H, Su H, Chen K, Yan J. FTO overexpression inhibits apoptosis of hypoxia/reoxygenation-treated myocardial cells by regulating m6A modification of Mhrt. Mol Cell Biochem. 2021;476(5):2171-2179. doi:10.1007/s11010-021-04069-6
9. Zhang B, Jiang H, Wu J, et al. m6A demethylase FTO attenuates cardiac dysfunction by regulating glucose uptake and glycolysis in mice with pressure overload-induced heart failure. Signal Transduct Target Ther. 2021;6(1):377. Published 2021 Nov 2. doi:10.1038/s41392-021-00699-w
10. Cui Y, Wang P, Li M, et al. Cinnamic acid mitigates left ventricular hypertrophy and heart failure in part through modulating FTO-dependent N6-methyladenosine RNA modification in cardiomyocytes. Biomed Pharmacother. 2023;165:115168. doi:10.1016/j.biopha.2023.115168