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

Abstract

Cardiovascular diseases lead the mortality and morbidity disease metrics worldwide. A multitude of chemical base modifications in ribonucleic acids (RNAs) have been linked with key events of cardiovascular diseases and metabolic disorders. Named either RNA epigenetics or epitranscriptomics, the post-transcriptional RNA modifications, their regulatory pathways, components, and downstream effects substantially contribute to the ways our genetic code is interpreted. Here we review the accumulated discoveries to date regarding the roles of the two most common epitranscriptomic modifications, N6-methyl-adenosine (m6A) and adenosine-to-inosine (A-to-I) editing, in cardiovascular disease.

Keywords: A-to-I editing; N6-methyladenosine; atherosclerosis; cardiac regeneration; cardiovascular medicine; epitranscriptomics; ischemic heart disease.

Conflict of interest statement

The authors declare no competing interests.

© 2022 The Author(s).

Figures

Graphical abstract

Figure 1

Depiction of the contributors responsible for A-to-I editing and m6A modification, respective downstream effectors, and the key effects on RNA biology ∗Inositol hexakisphosphate (cofactor). ∗∗While ENDOV has been recently suggested to protect inosine-bound transcripts from degradation in vivo, it acts to target them for cleavage in vitro (see section “atherosclerosis”). While red-colored molecules harbor catalytic activity, the light-colored molecules act as non-catalytic subunits. The abbreviations are listed within the text.

Figure 2

A schematic overview of the studies assessing m6A modification and A-to-I editing in CVDs to date Colored numbers denote specific original publication reference. The black-colored reference forwards interested readers to a recent review specifically discussing the role epitranscriptomic modifications in brain physiology and diseases, which is out of topic of the present review.

Figure 3

The unveiled molecular interactions involving m6A and A-to-I or respective key regulators in common vasculopathies and non-malignant angiogenesis The number of blunted arrows for a given pathway can be used as a guide for assessing the overall effect of the pathway. ∗METTL3 has been described both as proatherogenic and antiatherogenic factor in endothelium subjected to oscillatory shear stress, see later discussion in section “atherosclerosis.” ∗∗The direct role of m6A upregulating the respective downstream miRNAs remains putative. The role of m6A and A-to-I editing in atherosclerosis pathophysiology is presented in greater detail in Figures 6 and 7. References are listed within Table S4 according to molecular pathways illustrated here. PM2.5, fine particulate matter, diameter <2.5 μm; SULF2, sulfatase 2.

Figure 4

The unveiled molecular interactions involving m6A modification or its key regulators according to various stages of IHD pathophysiology The number of blunted arrows for a given pathway can be used as a guide for assessing the overall effect of the pathway. The break within the blue rounded arrow represents the putative regenerative ability of adult mammals (in rodents and perhaps in humans, the relevant ability for myocardium to regenerate is lost within the first week of life). References are listed in Table S4 according to molecular pathways illustrated here. AGO2, argonaute RNA-induced silencing complex (RISC) catalytic component 2; CHOP, C/EBP homologous protein; CTNND1, catenin delta 1; CTSL, cathepsin L; KDM5A, lysine demethylase 5A; MYH9, myosin heavy chain 9; NPPA, natriuretic peptide A; SLC7A5, solute carrier family 7 member 5.

Figure 5

Summary of accumulated discoveries regarding m6A and its key regulators in obesity-related and diabetic cardiomyopathy, cardiomyocyte inflammation, and death Red upward arrows indicate upregulated expression, red horizontal arrows indicate activation, blue downward arrows denote downregulated expression, and blunt-end arrows indicate inhibition. Brown, green, and blue ellipses denote RNAs, proteins, and m6A regulators, respectively. Red ellipse: "p" denotes phosphorylation, "u" ubiquitination. FAs, fatty acids; IL-6, interleukin-6.

Figure 6

A summary of the key discoveries regarding adenosine-targeted epitranscriptomic alterations in atherosclerosis and arteriosclerosis to date Red upward arrows indicate upregulated expression, red horizontal arrows indicate activation, blue downward arrows denote downregulated expression, and blue blunt-end arrows indicate inhibition. . Brown, green, and blue ellipses denote RNAs, proteins, and m6A regulators, respectively. Question mark represents a putative connection based on evidence from other than atherosclerotic tissues. ∗METTL3 has been associated with contrasting functions and expression responses in a model of early atherosclerosis with endothelial oscillatory shear stress. See section “atherosclerosis” for further discussion. The abbreviations are listed within the text.

Figure 7

Currently known molecular mechanisms involving m6A and its key regulators during macrophage inflammation and foam cell formation Red upward arrows indicate upregulated expression, red horizontal arrows indicate activation, blue downward arrows denote downregulated expression, and blue blunt-end arrows indicate inhibition. Dashed line represents putative relationship. Brown, green, and blue ellipses denote RNAs, proteins, and m6A regulators, respectively. Red ellipse denotes phosphorylation. ABCA1, ATP-binding cassette subfamily A member 1; ABCG1, ATP-binding cassette subfamily G member 1; AMPKα, AMP-activated protein kinase α; CXCL10, C-X-C motif chemokine ligand 10; PPAR-γ, peroxisome proliferator-activated receptor γ; SR-A1, scavenger receptor class A member 1; STAT1, signal transducer and activator of transcription 1.