Cardiovasc Drugs Ther

2022

DOI: 10.1007/s10557-022-07348-6

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Silencing METTL3 Stabilizes Atherosclerotic Plaques by Regulating the Phenotypic Transformation of Vascular Smooth Muscle Cells via the miR-375-3p/PDK1 Axis

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A Modification and Osteogenesis Of Bmscs1

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Cited by 16 publications

(13 citation statements)

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“…32–35 Using shRNA targeting Mettl3 (pLV-shMettl3), Chien et al 19 demonstrated that under disturbed flow and oscillatory shear stress, METTL3 upregulated Nlrp1 and downregulates Klf4 in endothelial cells to elicit atherogenic responses. Chen et al 20 reported that knockdown of METTL3 decreased vascular smooth muscle cell phenotype transformation and made plaques more stable via the miR-375-3p/ Pdk1 axis using Mettl3 shRNA. However, studies evaluating how conditional deletion of Mettl3 in myeloid cells regulates atherosclerosis in vivo are lacking.…”

Section: Discussionmentioning

confidence: 99%

“…Using shRNA administration with Mettl3 knockdown, METTL3 was shown to influence the atherosclerosis progression by regulating endothelial cell and smooth muscle cell functions. 19,20 Nonetheless, the role of METTL3 in macrophages in atherosclerosis has not been fully elucidated and direct evidence from myeloid cell–specific Mettl3 knockout mice in vivo was lacking to date.…”

mentioning

confidence: 99%

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METTL3 (Methyltransferase Like 3)-Dependent N6-Methyladenosine Modification on Braf mRNA Promotes Macrophage Inflammatory Response and Atherosclerosis in Mice

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BACKGROUND: Atherosclerosis is a chronic inflammatory disease, in which macrophages determine the progression of atherosclerotic plaques. However, no studies have investigated how METTL3 (methyltransferase like 3) in macrophages affects atherosclerotic plaque formation in vivo. Additionally, whether Braf is modified by METTL3-dependent N6-methyladenosine (m6A) methylation remains unknown. METHODS: We analyzed single-cell sequencing data of atherosclerotic plaques in mice fed with a high fat diet for different periods. Mettl3 fl/fl Lyz 2 cre Apoe –/– mice and littermate control Mettl3 fl/fl Apoe –/– mice were generated and fed high fat diet for 14 weeks. In vitro, we stimulated peritoneal macrophages with ox-LDL (oxidized low-density lipoprotein) and tested the mRNA and protein expression levels of inflammatory factors and molecules regulating ERK (extracellular signal-regulated kinase) phosphorylation. To find METTL3 targets in macrophages, we performed m6A-methylated RNA immunoprecipitation sequencing and m6A-methylated RNA immunoprecipitation-qPCR. Further, point mutation experiments were used to explore m6A-methylated adenine. Using RNA immunoprecipitation assay, we explored m6A methylation-writing protein bound to Braf mRNA. RESULTS: In vivo, METTL3 expression in macrophages increased with the progression of atherosclerosis. Myeloid cell–specific METTL3 deletion negatively regulated atherosclerosis progression and the inflammatory response. In vitro, METTL3 knockdown or knockout in macrophages attenuated ox-LDL-mediated ERK phosphorylation rather than JNK (c-Jun N-terminal kinase) and p38 phosphorylation and reduced the level of inflammatory factors by affecting BRAF protein expression. The negative regulation of inflammation response caused by METTL3 knockout was rescued by overexpression of BRAF. In mechanism, METTL3 targeted adenine (39725126 in chromosome 6) on the Braf mRNA. Then, YTHDF1 could bind to m6A-methylated Braf mRNA and promote its translation. CONCLUSIONS: Myeloid cell–specific Mettl3 deficiency suppressed hyperlipidemia-induced atherosclerotic plaque formation and attenuated atherosclerotic inflammation. We identified Braf mRNA as a novel target of METTL3 in the activation of the ox-LDL-induced ERK pathway and inflammatory response in macrophages. METTL3 may represent a potential target for the treatment of atherosclerosis.

“…32–35 Using shRNA targeting Mettl3 (pLV-shMettl3), Chien et al 19 demonstrated that under disturbed flow and oscillatory shear stress, METTL3 upregulated Nlrp1 and downregulates Klf4 in endothelial cells to elicit atherogenic responses. Chen et al 20 reported that knockdown of METTL3 decreased vascular smooth muscle cell phenotype transformation and made plaques more stable via the miR-375-3p/ Pdk1 axis using Mettl3 shRNA. However, studies evaluating how conditional deletion of Mettl3 in myeloid cells regulates atherosclerosis in vivo are lacking.…”

Section: Discussionmentioning

confidence: 99%

“…Using shRNA administration with Mettl3 knockdown, METTL3 was shown to influence the atherosclerosis progression by regulating endothelial cell and smooth muscle cell functions. 19,20 Nonetheless, the role of METTL3 in macrophages in atherosclerosis has not been fully elucidated and direct evidence from myeloid cell–specific Mettl3 knockout mice in vivo was lacking to date.…”

mentioning

confidence: 99%

METTL3 (Methyltransferase Like 3)-Dependent N6-Methyladenosine Modification on Braf mRNA Promotes Macrophage Inflammatory Response and Atherosclerosis in Mice

¹

,

²

,

³

et al. 2023

View full text Add to dashboard Cite

BACKGROUND: Atherosclerosis is a chronic inflammatory disease, in which macrophages determine the progression of atherosclerotic plaques. However, no studies have investigated how METTL3 (methyltransferase like 3) in macrophages affects atherosclerotic plaque formation in vivo. Additionally, whether Braf is modified by METTL3-dependent N6-methyladenosine (m6A) methylation remains unknown. METHODS: We analyzed single-cell sequencing data of atherosclerotic plaques in mice fed with a high fat diet for different periods. Mettl3 fl/fl Lyz 2 cre Apoe –/– mice and littermate control Mettl3 fl/fl Apoe –/– mice were generated and fed high fat diet for 14 weeks. In vitro, we stimulated peritoneal macrophages with ox-LDL (oxidized low-density lipoprotein) and tested the mRNA and protein expression levels of inflammatory factors and molecules regulating ERK (extracellular signal-regulated kinase) phosphorylation. To find METTL3 targets in macrophages, we performed m6A-methylated RNA immunoprecipitation sequencing and m6A-methylated RNA immunoprecipitation-qPCR. Further, point mutation experiments were used to explore m6A-methylated adenine. Using RNA immunoprecipitation assay, we explored m6A methylation-writing protein bound to Braf mRNA. RESULTS: In vivo, METTL3 expression in macrophages increased with the progression of atherosclerosis. Myeloid cell–specific METTL3 deletion negatively regulated atherosclerosis progression and the inflammatory response. In vitro, METTL3 knockdown or knockout in macrophages attenuated ox-LDL-mediated ERK phosphorylation rather than JNK (c-Jun N-terminal kinase) and p38 phosphorylation and reduced the level of inflammatory factors by affecting BRAF protein expression. The negative regulation of inflammation response caused by METTL3 knockout was rescued by overexpression of BRAF. In mechanism, METTL3 targeted adenine (39725126 in chromosome 6) on the Braf mRNA. Then, YTHDF1 could bind to m6A-methylated Braf mRNA and promote its translation. CONCLUSIONS: Myeloid cell–specific Mettl3 deficiency suppressed hyperlipidemia-induced atherosclerotic plaque formation and attenuated atherosclerotic inflammation. We identified Braf mRNA as a novel target of METTL3 in the activation of the ox-LDL-induced ERK pathway and inflammatory response in macrophages. METTL3 may represent a potential target for the treatment of atherosclerosis.

“…Similar phenomenon was observed between METTL14 and miR-873 [ 60 ]. However, some anti-osteogenic miRNAs, such as miR-143-3p [ 61 – 66 ], miR-25-3p [ 67 – 71 ], miR-146a-5p [ 72 – 74 ], miR-30b-5p [ 75 , 76 ], miR-93-5p [ 77 , 78 ], miR-375-3p [ 79 , 80 ], and miR-221/222 [ 81 ], were also modulated by m 6 A modification, which stimulates the miRNA mature. These miRNAs could negatively regulate the osteogenic process by binding mRNAs of pro-osteogenic genes.…”

Section: A Modification and Osteogenesis Of Bmscsmentioning

confidence: 99%

N6-Methyladenosine in Cell-Fate Determination of BMSCs: From Mechanism to Applications

Zhang,

Li,

Wang

et al. 2024

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The methylation of adenosine base at the nitrogen-6 position is referred to as “N6-methyladenosine (m 6 A)” and is one of the most prevalent epigenetic modifications in eukaryotic mRNA and noncoding RNA (ncRNA). Various m 6 A complex components known as “writers,” “erasers,” and “readers” are involved in the function of m 6 A. Numerous studies have demonstrated that m 6 A plays a crucial role in facilitating communication between different cell types, hence influencing the progression of diverse physiological and pathological phenomena. In recent years, a multitude of functions and molecular pathways linked to m 6 A have been identified in the osteogenic, adipogenic, and chondrogenic differentiation of bone mesenchymal stem cells (BMSCs). Nevertheless, a comprehensive summary of these findings has yet to be provided. In this review, we primarily examined the m 6 A alteration of transcripts associated with transcription factors (TFs), as well as other crucial genes and pathways that are involved in the differentiation of BMSCs. Meanwhile, the mutual interactive network between m 6 A modification, miRNAs, and lncRNAs was intensively elucidated. In the last section, given the beneficial effect of m 6 A modification in osteogenesis and chondrogenesis of BMSCs, we expounded upon the potential utility of m 6 A-related therapeutic interventions in the identification and management of human musculoskeletal disorders manifesting bone and cartilage destruction, such as osteoporosis, osteomyelitis, osteoarthritis, and bone defect.

“…For example, miR-214 can lead to a reduction in contractile protein expression by increasing Smad7 levels and decreasing Smad3 phosphorylation, thus facilitating a shift in VSMC phenotype ( 58 ). Similarly, miR-375-3p targets PDK1, promoting phenotypic changes in VSMCs ( 59 ).…”

Section: Introductionmentioning

confidence: 99%

Elucidating VSMC phenotypic transition mechanisms to bridge insights into cardiovascular disease implications

Xin,

Zhang,

Lv

et al. 2024

Front. Cardiovasc. Med.

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Cardiovascular diseases (CVD) are the leading cause of death worldwide, despite advances in understanding cardiovascular health. Significant barriers still exist in effectively preventing and managing these diseases. Vascular smooth muscle cells (VSMCs) are crucial for maintaining vascular integrity and can switch between contractile and synthetic functions in response to stimuli such as hypoxia and inflammation. These transformations play a pivotal role in the progression of cardiovascular diseases, facilitating vascular modifications and disease advancement. This article synthesizes the current understanding of the mechanisms and signaling pathways regulating VSMC phenotypic transitions, highlighting their potential as therapeutic targets in cardiovascular disease interventions.

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