Trpm4 participates in aldosterone‐salt‐induced electrical atrial remodeling in mice

Abstract

Aldosterone plays a major role in atrial structural and electrical remodeling, in particular through Ca2+‐transient perturbations and shortening of the action potential. The Ca2+‐activated nonselective 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.