Mettl3 deficiency leads to the upregulation of Cav1.2 and increases arrhythmia susceptibility in mice
Methyltransferase-like 3 (Mettl3) is a component of methyltransferase complex that mediates m<sup>6</sup>A modification of RNAs, and participates in multiple biological processes. However, the role of Mettl3 in cardiac electrophysiology remains unknown. This study aims to explore the ven...
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| Format: | Article |
| Language: | English |
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China Science Publishing & Media Ltd.
2022-01-01
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| Series: | Acta Biochimica et Biophysica Sinica |
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| Online Access: | https://www.sciengine.com/doi/10.3724/abbs.2021025 |
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| author | Shi Ling Jin Xuexin Li Zheng Gong Rui Guo Yang Ma Jiudong Zhang Yang Cai Benzhi Yang Baofeng Gong Dongmei Pan Zhenwei |
| author_facet | Shi Ling Jin Xuexin Li Zheng Gong Rui Guo Yang Ma Jiudong Zhang Yang Cai Benzhi Yang Baofeng Gong Dongmei Pan Zhenwei |
| author_sort | Shi Ling |
| collection | DOAJ |
| description | Methyltransferase-like 3 (Mettl3) is a component of methyltransferase complex that mediates m<sup>6</sup>A modification of RNAs, and participates in multiple biological processes. However, the role of Mettl3 in cardiac electrophysiology remains unknown. This study aims to explore the ventricular arrhythmia susceptibility of Mettl3<sup>+/–</sup> mice and the underlying mechanisms. Mice were anesthetized with 2% avertin (0.1 mL/<sc>10 g</sc> body weight) for echocardiography and programmed electrical pacing. Whole-cell patch clamp technique was used to examine the electrophysiological property of cardiomyocytes. The expression of Cav1.2 was determined by qRT-PCR and western blot analysis. The m<sup>6</sup>A medication of mRNA was examined by MeRIP-Seq and MeRIP-qPCR. No differences are found in the morphology and function of the hearts between Mettl3<sup>+/–</sup> mice and wild-type (WT) controls. The QT and QTc intervals of Mettl3<sup>+/–</sup> mice are significantly longer. High-frequency electrical stimulation showed that heterozygous knockout of Mettl3 increases ventricular arrhythmia susceptibility. The whole-cell patch-clamp recordings showed that the APD is prolonged in Mettl3<sup>+/–</sup> ventricular myocytes and more EADs were observed. The density of I<sub>Ca-L</sub> is substantially increased in ventricular myocytes of Mettl3<sup>+/–</sup> mice. The pore-forming subunit of L-type calcium channel Cav1.2 is upregulated in Mettl3<sup>+/–</sup> mice, while the mRNA of its coding gene CACNA1C does not change. MeRIP-Seq and MeRIP-qPCR showed that the m<sup>6</sup>A methylation of CACNA1C mRNA is decreased in cultured Mettl3-knockdown cardiomyocytes and Mettl3<sup>+/–</sup> hearts. Collectively, deficiency of Mettl3 increases ventricular arrhythmia susceptibility due to the upregulation of Cav1.2 by reducing m<sup>6</sup>A modification on CACNA1C mRNA in mice. This study highlights the role of m<sup>6</sup>A modification in the regulation of cardiac electrophysiology. |
| first_indexed | 2024-03-11T12:25:58Z |
| format | Article |
| id | doaj.art-b05c54c16bac446082dd6f46efc601dc |
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| issn | 1672-9145 |
| language | English |
| last_indexed | 2024-03-11T12:25:58Z |
| publishDate | 2022-01-01 |
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| spelling | doaj.art-b05c54c16bac446082dd6f46efc601dc2023-11-06T09:02:45ZengChina Science Publishing & Media Ltd.Acta Biochimica et Biophysica Sinica1672-91452022-01-015419920810.3724/abbs.202102520d259ccMettl3 deficiency leads to the upregulation of Cav1.2 and increases arrhythmia susceptibility in miceShi Ling0Jin Xuexin1Li Zheng2Gong Rui3Guo Yang4Ma Jiudong5Zhang Yang6Cai Benzhi7Yang Baofeng8Gong Dongmei9Pan Zhenwei10["Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China"]["Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China"]["Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China"]["Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China"]["Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China"]["Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China"]["Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China"]["Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China"]["Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China","Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences (2019RU070), Harbin 150086, China"]["Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China"]["Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China","Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences (2019RU070), Harbin 150086, China","Key Laboratory of Cell Transplantation, the First Affiliated Hospital, Harbin Medical University, Harbin 150086, China"]Methyltransferase-like 3 (Mettl3) is a component of methyltransferase complex that mediates m<sup>6</sup>A modification of RNAs, and participates in multiple biological processes. However, the role of Mettl3 in cardiac electrophysiology remains unknown. This study aims to explore the ventricular arrhythmia susceptibility of Mettl3<sup>+/–</sup> mice and the underlying mechanisms. Mice were anesthetized with 2% avertin (0.1 mL/<sc>10 g</sc> body weight) for echocardiography and programmed electrical pacing. Whole-cell patch clamp technique was used to examine the electrophysiological property of cardiomyocytes. The expression of Cav1.2 was determined by qRT-PCR and western blot analysis. The m<sup>6</sup>A medication of mRNA was examined by MeRIP-Seq and MeRIP-qPCR. No differences are found in the morphology and function of the hearts between Mettl3<sup>+/–</sup> mice and wild-type (WT) controls. The QT and QTc intervals of Mettl3<sup>+/–</sup> mice are significantly longer. High-frequency electrical stimulation showed that heterozygous knockout of Mettl3 increases ventricular arrhythmia susceptibility. The whole-cell patch-clamp recordings showed that the APD is prolonged in Mettl3<sup>+/–</sup> ventricular myocytes and more EADs were observed. The density of I<sub>Ca-L</sub> is substantially increased in ventricular myocytes of Mettl3<sup>+/–</sup> mice. The pore-forming subunit of L-type calcium channel Cav1.2 is upregulated in Mettl3<sup>+/–</sup> mice, while the mRNA of its coding gene CACNA1C does not change. MeRIP-Seq and MeRIP-qPCR showed that the m<sup>6</sup>A methylation of CACNA1C mRNA is decreased in cultured Mettl3-knockdown cardiomyocytes and Mettl3<sup>+/–</sup> hearts. Collectively, deficiency of Mettl3 increases ventricular arrhythmia susceptibility due to the upregulation of Cav1.2 by reducing m<sup>6</sup>A modification on CACNA1C mRNA in mice. This study highlights the role of m<sup>6</sup>A modification in the regulation of cardiac electrophysiology.https://www.sciengine.com/doi/10.3724/abbs.2021025Mettl3m<sup>6</sup>A modificationarrhythmiaL-type calcium channel |
| spellingShingle | Shi Ling Jin Xuexin Li Zheng Gong Rui Guo Yang Ma Jiudong Zhang Yang Cai Benzhi Yang Baofeng Gong Dongmei Pan Zhenwei Mettl3 deficiency leads to the upregulation of Cav1.2 and increases arrhythmia susceptibility in mice Acta Biochimica et Biophysica Sinica Mettl3 m<sup>6</sup>A modification arrhythmia L-type calcium channel |
| title | Mettl3 deficiency leads to the upregulation of Cav1.2 and increases arrhythmia susceptibility in mice |
| title_full | Mettl3 deficiency leads to the upregulation of Cav1.2 and increases arrhythmia susceptibility in mice |
| title_fullStr | Mettl3 deficiency leads to the upregulation of Cav1.2 and increases arrhythmia susceptibility in mice |
| title_full_unstemmed | Mettl3 deficiency leads to the upregulation of Cav1.2 and increases arrhythmia susceptibility in mice |
| title_short | Mettl3 deficiency leads to the upregulation of Cav1.2 and increases arrhythmia susceptibility in mice |
| title_sort | mettl3 deficiency leads to the upregulation of cav1 2 and increases arrhythmia susceptibility in mice |
| topic | Mettl3 m<sup>6</sup>A modification arrhythmia L-type calcium channel |
| url | https://www.sciengine.com/doi/10.3724/abbs.2021025 |
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