Aiden Gannon

Background: Cardiovascular disease is the number one cause of death worldwide which includes heart failure (HF). HF represents the terminal stage of various cardiovascular diseases including poor cardiac performance and left ventricular dilatation.³ As of 2019, over 64 million people worldwide were afflicted with HF and in the United States the prevalence of HF has grown from 5 million in 2013 to 6.7 million in 2023. ¹ In addition, as the world’s population continues to age the prevalence of HF is expected to reach over 30% of the elderly population by 2030.¹ HF is associated with a poor prognosis and has a 5-year mortality rate of around 45%.¹ m6A modification is an evolutionarily conserved, reversible, site-specific RNA modification that alters mRNA stability and protein translation. Increased levels of m6A have been associated with HF^1,3-5 and its ability to be reversed and modified through use of writers and erasers suggested potential therapeutic targets for improving the prognosis of HF.³

Objective: In this narrative review, we explored the mechanisms by which m6A levels are increased in HF models and ways that modifying these levels affects outcomes.

Search Methods: An online search in the PubMed database was conducted from 2019 to 2024 using the following keywords: “m6A”, “Heart Failure”, “Epitranscriptome”, and “RNA modification”.

Results: Studies indicate that failing cardiac left ventricular tissue from pigs, rats, mice, and postmortem human models displayed increased levels of m6A modification.⁷ These levels can be achieved via overexpression of m6A writers, such as METTL 3 and METTL 14, or under expression of erasers, such as FTO.^7-11 Improving the expression of FTO led to decreased levels of m6A in RNA and slowed the progression of degeneration of cardiac myocytes in HF, while FTO knockout models displayed severely worse cardiovascular function in mice.^7,11 METTL3 overexpression increased m6A modification and stability in the mRNA of key apoptotic regulator Tenascin-C (TNC) which promotes myocardial infarction and eventual HF.⁹ METTL3 modification of m6A levels increased in response to hypertrophic stimuli and it was found that peaks in m6A were identified on “protein modifying enzymes” that notably include ryanodine receptor 2 and map3k6 kinase.¹⁰ However, knockouts of METTL3 displayed accelerated HF conditions in response to stress which highlights the delicate and intricate nature of m6A modification overall.¹⁰ Further analysis pinpointed that 24% of transcripts in HF models displayed differential methylation patterns.¹¹ The differentially methylated transcripts detected in the HF model were linked to metabolic processes and mitochondrial functions and hypermethylated transcripts were also involved in cardiac muscle development.¹¹

Conclusion: Studies have found that there are alterations in m6A modified RNA transcripts across HF models as a result of adjusted expression of m6A readers and writers. The delicate balance of maintaining m6A’s evolutionarily conserved function poses a difficult challenge if modified in wake of HF treatment, but ultimately it is possible to discover via additional research.

Works Cited:

1. Sikorski V, Vento A, Kankuri E; IHD-EPITRAN Consortium. Emerging roles of the RNA modifications N6-methyladenosine and adenosine-to-inosine in cardiovascular diseases. Mol Ther Nucleic Acids. 2022;29:426-461. Published 2022 Jul 20. doi:10.1016/j.omtn.2022.07.018
2. Roth GA, Mensah GA, Johnson CO, et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study [published correction appears in J Am Coll Cardiol. 2021 Apr 20;77(15):1958-1959]. J Am Coll Cardiol. 2020;76(25):2982-3021. doi:10.1016/j.jacc.2020.11.010
3. Zhang X, Cai H, Xu H, Dong S, Ma H. Critical roles of m6A methylation in cardiovascular diseases. Front Cardiovasc Med. 2023;10:1187514. Published 2023 May 19. doi:10.3389/fcvm.2023.1187514
4. Woudenberg T, Kruyt ND, Quax PHA, Nossent AY. Change of Heart: the Epitranscriptome of Small Non-coding RNAs in Heart Failure. Curr Heart Fail Rep. 2022;19(5):255-266. doi:10.1007/s11897-022-00561-2
5. Ye W, Lv X, Gao S, Li Y, Luan J, Wang S. Emerging role of m6A modification in fibrotic diseases and its potential therapeutic effect. Biochemical Pharmacology. 2023;218:115873. doi:https://doi.org/10.1016/j.bcp.2023.115873
6. ‌Goldstein D, Frishman WH. Diastolic Heart Failure. Cardiology in Review. Published online February 2020:1. doi:https://doi.org/10.1097/crd.0000000000000303
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. 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
9. Cheng H, Li L, Xue J, Ma J, Ge J. TNC Accelerates Hypoxia-Induced Cardiac Injury in a METTL3-Dependent Manner. Genes (Basel). 2023;14(3):591. Published 2023 Feb 26. doi:10.3390/genes14030591
10. Dorn LE, Lasman L, Chen J, et al. The N6-Methyladenosine mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy. Circulation. 2019;139(4):533-545. doi:10.1161/CIRCULATIONAHA.118.036146
11. 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
12. 1. Tang L, Wei X, Li T, et al. Emerging perspectives of RNA N6-methyladenosine (M6A) modification on immunity and autoimmune diseases. Frontiers. February 16, 2021. Accessed April 8, 2024. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.630358/full.