TRPM4 Participates in Aldosterone-Salt-Induced Electrical Atrial Remodeling in Mice

Aldosterone plays a major role in atrial structural and electrical remodeling, in particular through Ca(2+)-transient perturbations and shortening of the action potential. The Ca(2+)-activated non-selective cation channel Transient Receptor Potential Melastatin 4 (TRPM4) participates in atrial action potential. The aim of our study was to elucidate the interactions between aldosterone and TRPM4 in atrial remodeling and arrhythmias susceptibility. Hyperaldosteronemia, combined with a high salt diet, was induced in mice by subcutaneously implanted osmotic pumps during 4 weeks, delivering aldosterone or physiological serum for control animals. The experiments were conducted in wild type animals (Trpm4(+/+)) as well as Trpm4 knock-out animals (Trpm4(-/-)). The atrial diameter measured by echocardiography was higher in Trpm4(-/-) compared to Trpm4(+/+) animals, and hyperaldosteronemia-salt produced a dilatation in both groups. Action potentials duration and triggered arrhythmias were measured using intracellular microelectrodes on the isolated left atrium. Hyperaldosteronemia-salt prolong action potential in Trpm4(-/-) mice but had no effect on Trpm4(+/+) mice. In the control group (no aldosterone-salt treatment), no triggered arrythmias were recorded in Trpm4(+/+) mice, but a high level was detected in Trpm4(-/-) mice. Hyperaldosteronemia-salt enhanced the occurrence of arrhythmias (early as well as delayed-afterdepolarization) in Trpm4(+/+) mice but decreased it in Trpm4(-/-) animals. Atrial connexin43 immunolabelling indicated their disorganization at the intercalated disks and a redistribution at the lateral side induced by hyperaldosteronemia-salt but also by Trpm4 disruption. In addition, hyperaldosteronemia-salt produced pronounced atrial endothelial thickening in both groups. Altogether, our results indicated that hyperaldosteronemia-salt and TRPM4 participate in atrial electrical and structural remodeling. It appears that TRPM4 is involved in aldosterone-induced atrial action potential shortening. In addition, TRPM4 may promote aldosterone-induced atrial arrhythmias, however, the underlying mechanisms remain to be explored.