RNA modification by M6A methylation in cardiovascular diseases: Current trends and future directions

Jinglin Wang; Lingfeng Zha

doi:10.2478/fzm-2022-0023

RNA modification by M6A methylation in cardiovascular diseases: Current trends and future directions

doi: 10.2478/fzm-2022-0023

Jinglin Wang,
Lingfeng Zha^,

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

More Information

Corresponding author: Lingfeng Zha, E-mail: zhalf@hust.edu.cn

摘要

Abstract: N6-methyladenosine (M6A) is the most common modification in eukaryotic RNAs for the regulation of RNA transcription, processing, splicing, degradation, and translation. RNA modification by M6A is dynamically reversible, involving methylated transferase, demethylase, and methylated reading protein. M6A-mediated gene regulation involves cell differentiation, metastasis, apoptosis, and proliferation. Dysregulation of M6A can lead to various diseases. Cardiovascular disease (CVD) seriously endangers human health and brings great social burden. Seeking effective prevention and treatment strategies for CVD is a challenge to both fundamentalists and clinicians. Substantial evidence has suggested the key role of M6A modification in the development of CVDs. This review summarizes the mechanism of M6A RNA modification and the latest research progress in respect with its role in CVDs, including atherosclerosis, coronary artery disease, myocardial infarction and cardiac remodeling, myocardial ischemia-reperfusion injury, heart failure, hypertension, and aortic aneurysm, and the potential applications of the findings to CVDs, thereby providing new ideas and approaches for the diagnosis and therapy of CVDs.
- RNA modification /
- M6A methylation /
- cardiovascular disease /
- epigenetics

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Figure 1. M6A modification and its mechanisms involved in cardiovascular diseases

hnRNP, (nuclear inhomogeneous ribose protein); eIF, eukaryotic initiation factors; IGF2BPs, insulin like growth factor 2 mRNA-binding proteins; EGFR, epidermal growth factor receptor; JAK2, janus kinase 2; STAT3, (activator of transcription 3); FOXO1, forkhead box O1; ASVEC, atherosclerotic vascular endothelial cells; MI, myocardial infarction; PTEN. phosphatase and tensin homolog; SETD2, SET domain-containing 2; PASMCs, pulmonary artery smooth muscle cell; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1-α; STAT1, signal transducer and activator of transcription 1; USP12, ubiquitin specific proteinase 12; Ctnnd1, catenin delta 1; SERCA2a, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a; YAP, yes-associated protein; TFEB, transcription factor EB; ATF4, activating transcription factor 4.

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Table 1. The role of M6A regulators in cardiovascular diseases

Cardiovascular disease	M6A regulator	Related gene	Mechanism
Atherosclerosis /coronary artery disease	METTL3	EGFR	METTL3 mitigated endothelial atherogenic progression by M6A-dependent stabilization of EGFR mRNA^[62]
	METTL3	NLRP1/ KLF4	In the AS model, partial ligation of the carotid artery resulted in plaque formation and up-regulation of METTL3. Knockdown of METTL3 prevented the atherogenic process^[61]
	METTL3	STAT1	METTL3 promotes ox-LDL-triggered inflammatory responses in macrophages by interacting with STAT1 protein and mRNA^[58]
	METTL3	IRF-1/ hsa_circ_0029589	Overexpression of IRF-1 suppressed the expression of hsa_circ_0029589, but induced its M6A level along with the expression of METTL3 in macrophages. Overexpression of hsa_circ_0029589 or inhibition of METTL3 significantly increased the expression of hsa_circ_0029589 and attenuated macrophage pyroptosis^[59]
	METTL3	PGC-1	METTL3 modifies PGC-1α mRNA promoting mitochondrial dysfunction and ox-LDL-induced inflammation in monocytes^[57]
	METTL3	JAK2	METTL3 knockdown prevented AS progression by inhibiting JAK2/STAT3 pathway via IGF2BP1^[60]
	METTL14	FOXO1	METTL14 aggravated endothelial inflammation and AS by increasing FOXO1 M6A modification^[64]
	METTL14	miR-19a	METTL14 increased the M6A modification of pri-miR-19a and promoted the processing of mature miR-19a, thus promoting the proliferation and invasion of ASVEC^[63]
	FTO		Related to neointima formation^[56]
	ALKBH1	MIAT/ HIF1α	Silencing of ALKBH1 or HIF1α could rescue the ox-LDL-increased level of MIAT^[55]
	YTHDF1	NLRP1	The METTL3-mediated RNA hypermethylation up-regulated NLRP1 transcript through YTHDF1^[61]
	YTHDF2	KLF4	The METTL3-mediated RNA hypermethylation down-regulated KLF4 transcript through YTHDF2^[61]
	YTHDF2	PGC-1	METTL3 coordinated with YTHDF2 to suppress the expression of PGC-1α, as well as CYCS and NDUFC2 and reduced ATP production and OCR, which subsequently increased the accumulation of cellular and mitochondrial ROS and the levels of proinflammatory cytokines in inflammatory monocytes^[57]
	IGF2BP1	JAK2	METTL3 knockdown prevented AS progression by inhibiting JAK2/STAT3 pathway via IGF2BP1^[60]
Myocardial infarction/cardiac remodeling	METTL3		Inhibition of METTL3 completely eliminated the ability of cardiomyocytes to undergo hypertrophy when stimulated to grow, whereas increased expression of METTL3 promoted cardiomyocyte hypertrophy both in vitro and in vivo. Cardiac-specific METTL3 knockout mice shown morphological and functional signs of HF with aging and stress^[72]
	METTL3	Collagen-associated genes	Enforced expression of METTL3 promoted proliferation and fibroblast-to-myofibroblast transition and collagens accumulation. Silencing METTL3 reduced cardiac fibrosis induced by MI via inhibiting the activation of cardiac fibroblasts^[71]
	METTL3		USP12 was partially dependent on the stabilization of p300 to activate METTL3 expression and promoted myocardial hypertrophy^[73]
	METTL3	CHAPIR	The piRNA CHAPIR regulated cardiac hypertrophy and cardiac remodelling by controlling METTL3-dependent M6A of Parp10 mRNA^[74]
	METTL3	miR-143-3p	METTL3 deficiency resulted in heart regeneration after MI via METTL3-pri-miR-143-(miR-143)-Yap/Ctnnd1 axis^[76]
	ALKBH5	YAP	ALKBH5 regulated cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1^[77]
	YTHDF1	YAP	ALKBH5 regulated cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1^[77]
	YTHDC1	Titin	Cardiac-specific conditional YTHDC1 knockout led to obvious left ventricular chamber enlargement and severe systolic dysfunction. YTHDC1 induces DCM by abnormal splicing of Titin^[75]
Myocardial ischemia-reperfusion injury	METTL3	BAX /PTEN	Down-regulated in both young and elderly hearts. BAX and PTEN are target genes of METTL3 under iH/R stress^[81]
	METTL3	miR-25-3p/miR-873-5p	METTL3 up-regulated miR-25-3p and miR-873-5p to activate the PI3K/Akt pathway, leading to the suppression of I/R injury^[82]
	METTL3	TFEB	Silencing METTL3 enhanced autophagic flux and inhibited apoptosis in H/R-treated cardiomyocyte^[84]
	WTAP	ATF4	WTAP promoted myocardial H/R injury by increasing endoplasmic reticulum stress via regulating M6A modification of ATF4 mRNA^[83]
	FTO	SERCA2a	FTO decreased M6A level of SERCA2a mRNA, thus accelerating SERCA2a expression, maintaining calcium homeostasis and improving the energy metabolism of H/R cardiomyocytes^[79]
	ALKBH5		Ferritin nanocage loaded with ALKBH5 inhibitor improved the cardiac function and reduced the infarct size in AMI^[80]
Heart failure	FTO		Cardiomyocyte restricted knockout of FTO impaired mice cardiac function^[51]
	FTO		Up-regulated expression in HFpEF patients and HFpEF mice^[89]
	FTO		FTO weakened cardiac dysfunction by regulating glucose uptake and glycolysis in mice with pressure overload-induced HF^[90]
	FTO		FTO was decreased expression in failing mammalian hearts and hypoxic cardiomyocytes, thereby increasing M6A in RNA and decreasing cardiomyocyte contractile function. FTO overexpression decreased fibrosis and enhanced angiogenesis^[91]
	FTO	MHRT	FTO overexpression inhibited apoptosis of hypoxia/reoxygenation-treated myocardial cells by regulating M6A modification of MHRT^[92]
	YTHDF2	MYH7	YTHDF2 improved cardiac hypertrophy by regulating MYH7 mRNA decoy^[93]
Hypertension	METTL3		Down-regulated in postnatal HPH^[97]
	METTL3	PTEN	YTHDF2 recognized METTL3 mediated M6A modified PTEN mRNA and accelerated the degradation of PTEN, which resulting in over-proliferation of PASMC by activating PI3K/Akt signaling pathway^[99]
	METTL14		Down-regulated in postnatal HPH^[97]
	METTL14	SETD2	SEDT2/METTL14-mediated M6A methylation awakening resulted in hypoxia-induced PAH in mice^[100]
	FTO		Decreased expression of FTO in small PA of MCT-PAH rat^[97]
	FTO		Down-regulated in postnatal HPH^[97]
	ALKBH5		Down-regulated in postnatal HPH^[97]
	YTHDF1	MAGED1	YTHDF1 promoted PASMC proliferation and PH by improving MAGED1 translation^[98]
	YTHDF1		Increased expression of YTHDF1 in small PA of MCT-PAH rat^[97]
	YTHDF2	PTEN	YTHDF2 recognized METTL3 mediated M6A modified PTEN mRNA and accelerated the degradation of PTEN, which resulting in over-proliferation of PASMC by activating PI3K/Akt signaling pathway^[99]
Aortic aneurysm	METTL3	miR-34a	METTL3 induced AAA development and progression by modulating M6A-dependent primary miR-34a processing^[105]
	METTL14		Down-regulated expression in human AAA, low METTL14 expression was related to high WBC and CRP expression^[104]
	METTL14		Associated with inflammatory infiltration and neovascularization^[103]
	RBM15B		Up-regulated expression in human AAA^[104]
	FTO	KLF5	FTO expression promotes phenotype conversion of VSMC^[106]
	FTO		Associated with aneurysm smooth muscle cells^[103]
	YTHDF3		YTHDF3 was associated with a greater risk of rupture and a strong association with macrophage infiltration^[103]
	HNRNPC		Down-regulated expression in human AAA^[104]
Other cardiovascular diseases	FTO		Overexpression FTO can reduce cardiac fibrosis and myocardial cell hypertrophy^[107]
	FTO	CD36	FTO knockdown affects the stability of CD36 mRNA and thus reduces the expression of CD36 and inhibits palmitic acid-induced cardiac inflammation^[108]
	FTO	IL-6/TNF-α	FTO knockdown in rat cardiomyocyte up-regulated M6A RNA methylation and expression of IL-6 and TNF-α ^[109]
EGFR, epidermal growth factor receptor; M6A, N6-methyladenosine; NLRP1, NLR family pyrin domain containing 1; KLF4, kruppel-like factor 4; AS, atherosclerosis; STAT1, signal transducer and activator of transcription 1; PGC-1α, proliferator-activated receptor γ coactivator 1-α; JAK2, janus kinase 2; STAT3, signal transducer and activator of transcription 3; IGF2BPs, insulin like growth factor 2 mRNA-binding proteins; FOXO1, forkhead box O1; ASVEC, atherosclerotic vascular endothelial cells; HIF1α, hypoxia inducible factor 1α; OCR, oxygen consumption rate; ROS, reactive oxygen species; YAP, yes-associated protein; HF, heart failure; MI, myocardial infarction; USP12, ubiquitin specific proteinase 12; PTEN, phosphatase and tensin homolog; TFEB, transcription factor EB; H/R: hypoxia/reoxygenation; BAX: BCL-2-associated X; SERCA2a, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a; AMI, acute myocardial infarction; HFpEF, heart failure with preserved ejection fraction; HPH, hypoxia mediated pulmonary hypertension; SETD2, SET domain-containing 2; MAGED1, melanoma antigen D1; AAA, abdominal aortic aneurysm; KLF5, kruppel-like factor 5; M6A, N6-methyladenosine.

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