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摘要
To investigate the regulation of N6- methyladenosine ( m6A ) modification on L-type calcium channels in atrial myocytes under high hydrostatic pressure, mediated by methyltransferase-like protein 3 ( METTL3 ). Methods C57BL/6J mice were randomly assigned to the control group and the hypertension group ( treated with continuous administration of angiotensin for four weeks ). Masson staining was used to observe the fibrosis of mouse atrial tissue, while dot blot assay and Western blot were used to detect the levels of m6A, METTL3, and Cavi1 2 in the atrial tissue. A high hydrostatic pressure model was constructed using the HL-1 cell line cultured in vitro, and METTL3 was intervened to observe changes in m6A expression levels, METTL3 and Cavi1 2 levels in cells,and action potential duration ( APD ) and L-type calcium current ( ICa,L ) were detected using whole-cell patch clamp. Results Compared to the control group, the hypertension group showed disordered atrial myocyte morphology, increased interstitial fibrosis, significant increased m6A content and METTL3 expression levels in the atrial tissue, and decreased expression of ion channel protein Cavi1 2. In HL-1 cells cultured in vitro,increasing hydrostatic pressure ( 0, 20, 40 mmHg ) up-regulated m6 A and METTL3 expression levels, down-regulated Cavi1 2, and these changes were reversed with STM2457 and si-METTL3. Furthermore, specific METTL3 inhibitor STM2457 reversed the shortening of APD and the decrease of I Ca,L peak density in HL-1 cells caused by high hydrostatic pressure, while METTL3 directly bound to CACNA1C. Conclusion METTL3- mediated m6A modification might directly regulate CACNA1C to participate in electrical remodeling of atrial myocytes under high hydrostatic pressure. ? 2023 Publication Centre of Anhui Medical University.
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