Metformin therapy confers cardioprotection against the remodeling of gap junction in tachycardia-induced atrial fibrillation dog model

Abstract

ObjectiveMetformin, introduced in 1957, is widely used as an anti-diabetic drug and has considerable benefits in cardiovascular disease reportedly, dependent or independent on its glucose-lowering effects. Aim of this study was to investigate the effect of metformin on gap junction and the inducibility of AF. MethodsBeagle dogs were subjected to acute or chronic pacing at right atrial appendage by a pacemaker to develop an AF model and electrophysiological parameters were measured. In vitro study, a cell fast pacing model was developed by CardioExcyte 96. We performed Western blot, histology immunohistochemical staining and electron microscopy to detect the effect of metformin. ResultsIn chronic AF model, the inducibility and duration of AF increased obviously after pacing for 6 weeks compared with sham-operated group (Inducibility, 3.33 ± 5.77 vs. 85.33 ± 7.89%, P<0.0001; Duration, 0.8 ± 0.84 vs. 11 ± 2.67 ms, P<0.0001). Effective refractory periods (ERP) decreased at left and right left atrium and atrial appendages compared with sham-operated group (123.95 ± 6.57 vs. 89.96 ± 7.39 ms P<0.0001). Metformin attenuated the pacing-induced increase in EPR (89.96 ± 7.39 vs. 105.83 ± 7.45 ms, P<0.05), AF inducibility and AF duration (Inducibility, 85.33 ± 7.89 vs. 64.17 ± 7.36%, Duration, 11 ± 2.67 vs. 8.62 ± 1.15 ms, P<0.05). The expression of Cx43 shows a significant downregulation(about 38%, P<0.001) after chronic pacing and treating with metformin could alleviate this decrease(P<0.01). However, the effect of metformin in acute pacing model is limited. The immunohistochemical staining of cardiac tissue also shown that there is more lateralized Cx43 under pacing condition (87.67 ± 2.52 vs. 60.8 ± 9.13%, P<0.005). These pacing-induced lateralize Cx43 could be alleviated by the metformin (48.4 ± 8.62 vs. 60.8 ± 9.13%, P<0.05). Additionally, metformin could affect the interactions of ZO-1 with p-Src/Cx43 via decrease the abnormal cAMP level after pacing (84.04 ± 4.58 vs. 69.34 ± 4.5 nmol/L, P<0.001). ConclusionsMetformin could alleviate the vulnerability of AF and attenuate the downregulation of gap junction under pacing condition via AMPK pathway and decreasing the P-Src level.