Decreased METTL3 in atrial myocytes promotes atrial fibrillation.

Abstract

Aims: Methyltransferase like 3 (METTL3) plays a crucial role in cardiovascular diseases, but its involvement in atrial fibrillation (AF) remains unclear. The study aims to explore the relationship between METTL3 and AF in atrial myocytes.

Methods and results: The protein level of METTL3 was evaluated in left atrial appendages (LAAs) from patients with persistent AF and in experimental AF models. cAMP-responsive element modulator (CREM) transgenic mice and CaCl2-acetylcholine (ACh)-injected mice were used as AF mice models. Methyltransferase like 3 was globally and atrial conditionally deleted in vivo to assess its role in AF. Confocal fluorescence microscopy was employed to examine calcium handling in atrial myocytes. Methylated RNA immunoprecipitation sequencing was performed to identify the downstream target genes of METTL3. Methyltransferase like 3 protein and RNA N6-methyladenosine (m6A) modification levels were significantly reduced in the LAAs of patients with AF and experimental AF models. Genetic inhibition of METTL3 promoted the development of AF in CREM transgenic mice and CaCl2-ACh-injected mice. Knockdown of METTL3 in atrial myocytes resulted in enhanced calcium handling. Reduced METTL3 levels increased SR Ca2+-ATPase Type 2a activity by up-regulating protocadherin gamma subfamily A, 10. Decreased METTL3 protein in atrial myocytes was attributed to down-regulation of cAMP-responsive element-binding protein 1/ubiquitin-specific peptidase 9 X-linked axis.

Conclusion: Our study established the pathophysiological role of METTL3 involved in the development of AF and provided a potential mechanism-based target for its treatment.