Résumé
Abstract only Transient Receptor Potential Melastatin-7 (TRPM7) is a divalent permeant channel-kinase of unknown function. It is concentrated in myocardium during embryonic development, and TRPM7-like current has been reported in adult ventricular myocytes. In atrial cardiac fibroblasts, TRPM7 has been implicated in fibrogenesis in patients with atrial fibrillation, however its function in ventricular myocardium is unexplored. We tested the hypothesis that TRPM7 is required for ventricular function by crossing TRPM7fl/- mice with the cardiac-targeted αMHC-Cre line (αMHC-TRPM7 KO). We show that TRPM7 forms a functional current in adult murine ventricular cardiomyocytes and demonstrate that ∼50% of αMHC-TRPM7 KO mice develop a cardiomyopathy with left ventricular dysfunction and cardiac hypertrophy, associated with heart block and impaired ventricular repolarization. This phenotype is associated with robust elevations in mRNA of Postn, Nppa, Timp1, Acta and reductions in Hdac9, Kcnv2, Kcnj3, Kcnd2, Lgi1 and Hcn4. Consistent with mRNA expression analysis and the observed electrical remodeling, patch-clamp of αMHC-Cre-TRPM7 KO ventricular myocytes (RV and LV) reveals significant action potential prolongation (2.5 to 4-fold increase in APD50) due to a 2 to 4-fold reduction in transient outward current (Ito, encoded by Kcnd2). Similarly, the funny current (If), encoded by Hcn4, is diminished 4-fold in atrioventricular nodal cells isolated from αMHC-Cre-Trpm7 KO hearts, accounting for the observed heart block. The ∼50% of αMHC-Cre-Trpm7 KO mice that do not develop cardiomyopathy are devoid of heart block, show normal expression levels of hypertrophy genes Postn, Nppa, and Acta, but continue to show significant reductions in Kcnd2, Lgi1, Kcnj3, Kcnv2, and Hdac9 expression. In conclusion, these results demonstrate that cardiac-targeted TRPM7 deletion dysregulates the expression of ion channels important for cardiomyocyte repolarization (Kcnd2) and atrioventricular conduction (Hcn4), leading to impaired ventricular repolarization and heart block in mice. The observed cardiomyopathy may arise from hemodynamic stresses secondary to chronic bradycardia from heart block in the setting of down-regulated histone deacetylase 9 (HDAC9).