Role of m6A RNA methylation in cardiovascular disease (Review)

Yuhan Qin, Linqing Li, Erfei Luo, Jiantong Hou, Gaoliang Yan, Dong Wang, Yong Qiao, Chengchun Tang, Yuhan Qin, Linqing Li, Erfei Luo, Jiantong Hou, Gaoliang Yan, Dong Wang, Yong Qiao, Chengchun Tang

Abstract

N6‑methyladenosine (m6A) is the most prevalent and abundant type of internal post‑transcriptional RNA modification in eukaryotic cells. Multiple types of RNA, including mRNAs, rRNAs, tRNAs, long non‑coding RNAs and microRNAs, are involved in m6A methylation. The biological function of m6A modification is dynamically and reversibly mediated by methyltransferases (writers), demethylases (erasers) and m6A binding proteins (readers). The methyltransferase complex is responsible for the catalyzation of m6A modification and is typically made up of methyltransferase‑like (METTL)3, METTL14 and Wilms tumor 1‑associated protein. Erasers remove methylation by fat mass and obesity‑associated protein and ALKB homolog 5. Readers play a role through the recognition of m6A‑modified targeted RNA. The YT521‑B homology domain family, heterogeneous nuclear ribonucleoprotein and insulin‑like growth factor 2 mRNA‑binding protein serve as m6A readers. The m6A methylation on transcripts plays a pivotal role in the regulation of downstream molecular events and biological functions, such as RNA splicing, transport, stability and translatability at the post‑transcriptional level. The dysregulation of m6A modification is associated with cancer, drug resistance, virus replication and the pluripotency of embryonic stem cells. Recently, a number of studies have identified aberrant m6A methylation in cardiovascular diseases (CVDs), including cardiac hypertrophy, heart failure, arterial aneurysm, vascular calcification and pulmonary hypertension. The aim of the present review article was to summarize the recent research progress on the role of m6A modification in CVD and give a brief perspective on its prospective applications in CVD.

Figures

Figure 1
Figure 1
Reversible m6A modification on mRNA. The adenosine (A) bases reside in mRNA could be methylated to form N6-methyladenosine (m6A) by the large MTC writer complex composed of the METTL3-METTL14-WTAP core component and other regulatory cofactors or by METTL16 alone. This enzymatic reaction uses S-adenosylmethionine (SAM) as a methyl donor. m6A could be recognized by m6A binding proteins (readers) to affect mRNA fate, or could be reversibly removed by m6A eraser proteins (i.e., FTO and ALKBH5). The demethylation process requires a-ketoglutaric acid (a-KG) and molecular oxygen (O2) as co-substrates and ferrous iron (Fe2+) as a cofactor (2). METTL, methyltransferase-like; FTO, fat mass and obesity-associated protein; ALKBH5, ALKB homolog 5.
Figure 2
Figure 2
The regulation of m6A modification. m6A is established by m6A methyltransferases ('writers') and removed by m6A demethylases ('erasers'). m6A readers are involved in multiple procedures of RNA metabolism through recognizing and binding to the m6A sites of RNAs. (A) HNRNPC plays an impor-tant role in the pre-mRNAs processing and structure switching. (B) HNRNPG modulates alternative splicing and structure switching. (C) HNRNPA2B1 accelerates primary miRNAs processing, alternative splicing, and structure switching. (D) YTHDC1 participates in the alternative splicing, nuclear export, and X chromosome silencing. (E) IGF2BP1/2/3 have a function to increase the stability of targeted mRNAs. (F) YTHDC2 promotes mRNAs translation. (G) YTHDF1 augments mRNAs translation. (H) YTHDF2 facilitates mRNAs decay. (I) YTHDF3 cooperates with YTHDF1 to increase mRNAs translation, and strengthens mRNAs decay mediated by YTHDF2 (33).
Figure 3
Figure 3
m6A modulators involved in cardiovascular disease and bioprocess. METTL3-mediated m6A modification is involved in cardiac hypertrophy by affecting kinase-regulated signaling pathway. Upregulated METTL3 and increased expression of paracrine factors, including VEGF, HGF, TGF-β, GM-CSF, bFGF and SDF-1 were found in ADSCs undergoing VSMC differentiation induction. The upregulation of METTL3 promoted the association of RNA binding protein HNRNPD with TFEB pre-mRNA and decreased TFEB expression, eventually impaired autophagic flux and enhancing apoptosis in ischemic heart disease. FTO mediated decreased expression of Calm1 and Serca2a are responsible for decreased heart contraction function and heart failure. Both elevated METTL14 and FTO are associated with inflammatory infiltration and neovascularization in abdominal aortic aneurysm. In addition, METTL3 mediated miR-34a maturation from pre-miR-34a, and then miR-34a negatively regulated the expression of SIRT1. m6A-modified Klotho mRNA plays a crucial role in vascular calcification. TPNS alleviated arterial restenosis through the downregulation of m6A methylation of p16. Decreased m6A modified circ Xpo6 and circ Tmtc3 are found in hypoxic pulmonary hypertension. Elevated METTL3, decreased FTO and ALKBH5 are involved in the development of hyperlipidemia resulted from LPS. Curcumin exerts a protective effect on LPS induced abnormal lipid metabolism. m6A associated plays a role in blood pressure, hyperlipidemia and coronary artery disease.

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