N6-Adenosine Methylation (m6A) RNA Modification: an Emerging Role in Cardiovascular Diseases

Chen, Yeshi; Ouyang, Xin; Novák, Petr; Zhou, Le; He, Ping; Yin, Kai

doi:10.1007/s12265-021-10108-w

Cited by 33 publications

(29 citation statements)

References 152 publications

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“…These data suggested that METTL3 regulated JAK2 expression by IGF2BP1 in HUVECs. In line with our data, previous studies also demonstrated that METTL3 could influence the development of diseases by regulating the expression of some genes under the cooperation with m6A reader IGF2BP1 ( Chen et al, 2021b ; Liu et al, 2020b ). For instance, Wei et al demonstrated that METTL3 cooperated with IGF2BP1 to increase the stability of transcription factor-activating enhancer-binding protein 2C (TFAP2C) mRNA, while the increase of TFAP2C expression level potentiated the resistance to cisplatin in seminoma ( Wei et al, 2020 ).…”

Section: Discussionsupporting

confidence: 91%

N6-Methyladenosine Methyltransferase METTL3 Promotes Angiogenesis and Atherosclerosis by Upregulating the JAK2/STAT3 Pathway via m6A Reader IGF2BP1

Dong

Shan

et al. 2021

Front. Cell Dev. Biol.

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Atherosclerosis (AS) is a life-threatening vascular disease. RNA N6-methyladenosine (m6A) modification level is dysregulated in multiple pathophysiologic processes including AS. In this text, the roles and molecular mechanisms of m6A writer METTL3 in AS progression were explored in vitro and in vivo. In the present study, cell proliferative, migratory, and tube formation capacities were assessed through CCK-8, Transwell migration, and tube formation assays, respectively. RNA m6A level was examined through a commercial kit. RNA and protein levels of genes were measured through RT-qPCR and western blot assays, respectively. VEGF secretion level was tested through ELISA assay. JAK2 mRNA stability was detected through actinomycin D assay. The relationship of METTL3, IGF2BP1, and JAK2 was investigated through bioinformatics analysis, MeRIP, RIP, RNA pull-down, and luciferase reporter assays. An AS mouse model was established to examine the effect of METTL3 knockdown on AS development in vivo. The angiogenetic activity was examined through chick chorioallantoic membrane assay in vivo. The results showed that METTL3 was highly expressed in ox-LDL-induced dysregulated HUVECs. METTL3 knockdown inhibited cell proliferation, migration, tube formation, and VEGF expression/secretion in ox-LDL-treated HUVECs, hampered AS process in vivo, and prevented in vivo angiogenesis of developing embryos. METTL3 positively regulated JAK2 expression and JAK2/STAT3 pathway in an m6A dependent manner in HUVECs. IGF2BP1 positively regulated JAK2 expression through directly binding to an m6A site within JAK2 mRNA in HUVECs. METTL3 knockdown weakened the interaction of JAK2 and IGF2BP1. METTL3 exerted its functions through JAK2/STAT3 pathway. In conclusion, METTL3 knockdown prevented AS progression by inhibiting JAK2/STAT3 pathway via IGF2BP1.

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Section: Discussionsupporting

confidence: 91%

N6-Methyladenosine Methyltransferase METTL3 Promotes Angiogenesis and Atherosclerosis by Upregulating the JAK2/STAT3 Pathway via m6A Reader IGF2BP1

Dong

Shan

et al. 2021

Front. Cell Dev. Biol.

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“…An increasing number of studies have shown that m6A RNA modification can affect the development and progression of AS ( Jian et al, 2020 ; Quiles-Jiménez et al, 2020 ; Chen et al, 2021 ). An AS study found that the expression levels of zinc finger NFX1-type containing 1 (ZNFX1) antisense RNA1 (ZFAS1) and the downstream ADAM10/RAB22A were important in the development of vascular inflammation and cholesterol metabolism ( Tang et al, 2020 ).…”

Section: Atherosclerosis and The M6a Ribonucleic Acid Modificationmentioning

confidence: 99%

The Role of m6A Ribonucleic Acid Modification in the Occurrence of Atherosclerosis

Cui

Zhang

et al. 2021

Front. Genet.

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The N6-methyladenosine (m6A) modification is the most abundant epitranscriptomic modification in eukaryotic messenger RNA (mRNA). The m6A modification process is jointly regulated by various enzymes and proteins, such as methyltransferases, demethylases and related m6A-binding proteins. The process is dynamic and reversible, and it plays an essential role in mRNA metabolism and various biological activities. Recently, an increasing number of researchers have confirmed that the onset and development of many diseases are closely associated with the molecular biological mechanism of m6A RNA methylation. This study focuses on the relationship between m6A RNA modification and atherosclerosis (AS). It thoroughly summarizes the mechanisms and processes of m6A RNA modification in AS-related cells and the relationships between m6A RNA modification and AS risk factors, and it provides a reference for exploring new targets for the early diagnosis and treatment of AS.

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“…m 6 A modification is involved in various physiological and pathological aspects in the context of CVD, including cardiomyocyte remodeling, cardiac hypertrophy and regulation of mitogen-activated protein kinases (MAPKs). Since its extensive role in CVD has been thoroughly reviewed elsewhere (17,18,(75)(76)(77), we will only briefly mention some of the most prevalent findings, while updating information where necessary. Of heightened interest is the METTL3-mediated modification, which has been heavily implicated in cardiac function and homeostasis (78).…”

Section: Rna Methylation Modificationsmentioning

confidence: 99%

“…As such, a number of reviews have already been published discussing the ever-expanding field of epitranscriptomic modifications, with a limited number focusing on their effects under the prism of cardiovascular disease (CVD). Most notable reviews have focused on N6-methyladenosine (m 6 A) modifications, as the most prevalent epitranscriptomic modification and its role in CVD (17,18). Although, Kumari et al (17) featured a section about m 6 A readers, Chen et al (18) also discussed the potential for m 6 A modification to influence CVD risk factors.…”

Section: Introductionmentioning

confidence: 99%

“…Most notable reviews have focused on N6-methyladenosine (m 6 A) modifications, as the most prevalent epitranscriptomic modification and its role in CVD (17,18). Although, Kumari et al (17) featured a section about m 6 A readers, Chen et al (18) also discussed the potential for m 6 A modification to influence CVD risk factors. Focusing more on clinical trials investigating epigenetic-sensitive drugs for heart failure (HF), Napoli et al (19) also outlined the discovery of epigenetic biomarkers and signatures of cardiac remodeling.…”

Section: Introductionmentioning

confidence: 99%

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Epitranscriptomics of cardiovascular diseases (Review)

et al. 2021

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RNA modifications have recently become the focus of attention due to their extensive regulatory effects in a vast array of cellular networks and signaling pathways. Just as epigenetics is responsible for the imprinting of environmental conditions on a genetic level, epitranscriptomics follows the same principle at the RNA level, but in a more dynamic and sensitive manner. Nevertheless, its impact in the field of cardiovascular disease (CVD) remains largely unexplored. CVD and its associated pathologies remain the leading cause of death in Western populations due to the limited regenerative capacity of the heart. As such, maintenance of cardiac homeostasis is paramount for its physiological function and its capacity to respond to environmental stimuli. In this context, epitranscriptomic modifications offer a novel and promising therapeutic avenue, based on the fine-tuning of regulatory cascades, necessary for cardiac function. This review aimed to provide an overview of the most recent findings of key epitranscriptomic modifications in both coding and non-coding RNAs. Additionally, the methods used for their detection and important associations with genetic variations in the context of CVD were summarized. Current knowledge on cardiac epitranscriptomics, albeit limited still, indicates that the impact of epitranscriptomic editing in the heart, in both physiological and pathological conditions, holds untapped potential for the development of novel targeted therapeutic approaches in a dynamic manner.

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N6-Adenosine Methylation (m6A) RNA Modification: an Emerging Role in Cardiovascular Diseases

Cited by 33 publications

References 152 publications

N6-Methyladenosine Methyltransferase METTL3 Promotes Angiogenesis and Atherosclerosis by Upregulating the JAK2/STAT3 Pathway via m6A Reader IGF2BP1

N6-Methyladenosine Methyltransferase METTL3 Promotes Angiogenesis and Atherosclerosis by Upregulating the JAK2/STAT3 Pathway via m6A Reader IGF2BP1

The Role of m6A Ribonucleic Acid Modification in the Occurrence of Atherosclerosis

Epitranscriptomics of cardiovascular diseases (Review)

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