RNA modifications in cardiovascular diseases, the potential therapeutic targets

Wu, Yihao; Zhan, Siyao; Xu, Yizhou; Gao, Xiangwei

doi:10.1016/j.lfs.2021.119565

Cited by 50 publications

(39 citation statements)

References 169 publications

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“…Similar to m6A modification, N1-Methyladenosine (m1A) is a typical type of RNA methylation, executing its biological functions through post-transcriptional regulation. Besides its role in tumorigenesis and many other biological processes ( 31 ), characteristic m1A modification and regulation have been reported in the pathophysiology of various cardiovascular diseases (CVDs) ( 17 , 32 , 33 ). Hence, it is of great significance to explore the role of m1A regulation in AAA occurrence and development.…”

Section: Discussionmentioning

confidence: 99%

N1-Methyladenosine (m1A) Regulation Associated With the Pathogenesis of Abdominal Aortic Aneurysm Through YTHDF3 Modulating Macrophage Polarization

Jiang

Zhang

et al. 2022

Front. Cardiovasc. Med.

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ObjectivesThis study aimed to identify key AAA-related m1A RNA methylation regulators and their association with immune infiltration in AAA. Furthermore, we aimed to explore the mechanism that m1A regulators modulate the functions of certain immune cells as well as the downstream target genes, participating in the progression of AAA.MethodsBased on the gene expression profiles of the GSE47472 and GSE98278 datasets, differential expression analysis focusing on m1A regulators was performed on the combined dataset to identify differentially expressed m1A regulatory genes (DEMRGs). Additionally, CIBERSORT tool was utilized in the analysis of the immune infiltration landscape and its correlation with DEMRGs. Moreover, we validated the expression levels of DEMRGs in human AAA tissues by real-time quantitative PCR (RT-qPCR). Immunofluorescence (IF) staining was also applied in the validation of cellular localization of YTHDF3 in AAA tissues. Furthermore, we established LPS/IFN-γ induced M1 macrophages and ythdf3 knockdown macrophages in vitro, to explore the relationship between YTHDF3 and macrophage polarization. At last, RNA immunoprecipitation-sequencing (RIP-Seq) combined with PPI network analysis was used to predict the target genes of YTHDF3 in AAA progression.ResultsEight DEMRGs were identified in our study, including YTHDC1, YTHDF1-3, RRP8, TRMT61A as up-regulated genes and FTO, ALKBH1 as down-regulated genes. The immune infiltration analysis showed these DEMRGs were positively correlated with activated mast cells, plasma cells and M1 macrophages in AAA. RT-qPCR analysis also verified the up-regulated expression levels of YTHDC1, YTHDF1, and YTHDF3 in human AAA tissues. Besides, IF staining result in AAA adventitia indicated the localization of YTHDF3 in macrophages. Moreover, our in-vitro experiments found that the knockdown of ythdf3 in M0 macrophages inhibits macrophage M1 polarization but promotes macrophage M2 polarization. Eventually, 30 key AAA-related target genes of YTHDF3 were predicted, including CD44, mTOR, ITGB1, STAT3, etc.ConclusionOur study reveals that m1A regulation is significantly associated with the pathogenesis of human AAA. The m1A “reader,” YTHDF3, may participate in the modulating of macrophage polarization that promotes aortic inflammation, and influence AAA progression by regulating the expression of its target genes.

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Section: Discussionmentioning

confidence: 99%

N1-Methyladenosine (m1A) Regulation Associated With the Pathogenesis of Abdominal Aortic Aneurysm Through YTHDF3 Modulating Macrophage Polarization

Jiang

Zhang

et al. 2022

Front. Cardiovasc. Med.

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“…This suggests that WTAP is essential to m6A modification (Duan et al, 2019). Furthermore, studies have confirmed that WTAP helps localize the m6A methyltransferase complex to the nuclear speckle and recruits it to the substrate RNA (Ping et al, 2014;Zhang W. et al, 2021;Wu et al, 2021).…”

Section: M6a Methyltransferase (Writer)mentioning

confidence: 96%

“…Methylation of adenine at the 6N position, commonly called m6A methylation ( Wu et al, 2021 ), was first discovered in 1974 in the messenger RNA (mRNA) of mammalian cells ( Desrosiers et al, 1974 ). Since its discovery, only few functional studies have been conducted on m6A modification because of a lack of reliable detection technologies.…”

Section: M6a Methylationmentioning

confidence: 99%

“…m6A modification is characterized by its dynamic reversibility, wide distribution, and highly conservative nature. As the most abundant RNA modification in eukaryotes, m6A modification is widely found in almost all types of RNA ( Wu S. et al, 2020 ), such as mRNA, transfer RNA (tRNA), circular RNA (circRNA), long non-coding RNA (lncRNA) RNA, and ribosomal RNA (rRNA), and more than 25% of human transcripts are modified by m6A ( Wu et al, 2021 ). m6A modification is not static but is instead dynamically regulated by m6A methyltransferases and demethylases ( Liu et al, 2014 ; Zhang W. et al, 2021 ).…”

Section: M6a Methylationmentioning

confidence: 99%

“…Additionally, FTO and ALKBH5 are both localized to the nucleus, and their knockdown significantly increases m6A-methylation levels ( Shen et al, 2015 ; Shen W. et al, 2021 ; Zhao Y. et al, 2021 ). The discovery of m6A demethylases revealed the reversibility of m6A modification, indicating that m6A modification is a dynamically regulated process ( Wu et al, 2021 ).…”

Section: M6a Methylationmentioning

confidence: 99%

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m6A Methylation in Cardiovascular Diseases: From Mechanisms to Therapeutic Potential

Liu

et al. 2022

Front. Genet.

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Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Recent studies have shown that n6-methyladenosine (m6A) plays a major role in cardiovascular homeostasis and pathophysiology. These studies have confirmed that m6A methylation affects the pathophysiology of cardiovascular diseases by regulating cellular processes such as differentiation, proliferation, inflammation, autophagy, and apoptosis. Moreover, plenty of research has confirmed that m6A modification can delay the progression of CVD via the post-transcriptional regulation of RNA. However, there are few available summaries of m6A modification regarding CVD. In this review, we highlight advances in CVD-specific research concerning m6A modification, summarize the mechanisms underlying the involvement of m6A modification during the development of CVD, and discuss the potential of m6A modification as a therapeutic target of CVD.

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HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m⁵C Methylation of Atf7 mRNA

Wang,

Li,

Zhou

et al. 2023

Advanced Science

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PIWI‐interacting RNAs (piRNAs) are highly expressed in various cardiovascular diseases. However, their role in cardiomyocyte death caused by ischemia/reperfusion (I/R) injury, especially necroptosis, remains elusive. In this study, a heart necroptosis‐associated piRNA (HNEAP) is found that regulates cardiomyocyte necroptosis by targeting DNA methyltransferase 1 (DNMT1)‐mediated 5‐methylcytosine (m5C) methylation of the activating transcription factor 7 (Atf7) mRNA transcript. HNEAP expression level is significantly elevated in hypoxia/reoxygenation (H/R)‐exposed cardiomyocytes and I/R‐injured mouse hearts. Loss of HNEAP inhibited cardiomyocyte necroptosis and ameliorated cardiac function in mice. Mechanistically, HNEAP directly interacts with DNMT1 and attenuates m5C methylation of the Atf7 mRNA transcript, which increases Atf7 expression level. ATF7 can further downregulate the transcription of Chmp2a, an inhibitor of necroptosis, resulting in the reduction of Chmp2a level and the progression of cardiomyocyte necroptosis. The findings reveal that piRNA‐mediated m5C methylation is involved in the regulation of cardiomyocyte necroptosis. Thus, the HNEAP‐DNMT1‐ATF7‐CHMP2A axis may be a potential target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.

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RNA modifications in cardiovascular diseases, the potential therapeutic targets

Cited by 50 publications

References 169 publications

N1-Methyladenosine (m1A) Regulation Associated With the Pathogenesis of Abdominal Aortic Aneurysm Through YTHDF3 Modulating Macrophage Polarization

N1-Methyladenosine (m1A) Regulation Associated With the Pathogenesis of Abdominal Aortic Aneurysm Through YTHDF3 Modulating Macrophage Polarization

m6A Methylation in Cardiovascular Diseases: From Mechanisms to Therapeutic Potential

HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m⁵C Methylation of Atf7 mRNA

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RNA modifications in cardiovascular diseases, the potential therapeutic targets

Cited by 50 publications

References 169 publications

N1-Methyladenosine (m1A) Regulation Associated With the Pathogenesis of Abdominal Aortic Aneurysm Through YTHDF3 Modulating Macrophage Polarization

N1-Methyladenosine (m1A) Regulation Associated With the Pathogenesis of Abdominal Aortic Aneurysm Through YTHDF3 Modulating Macrophage Polarization

m6A Methylation in Cardiovascular Diseases: From Mechanisms to Therapeutic Potential

HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m5C Methylation of Atf7 mRNA

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HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m⁵C Methylation of Atf7 mRNA