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

Cells. 2021 Mar 12;10(3):636. doi: 10.3390/cells10030636.

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 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.

Keywords: TRPM4; aldosterone; atria; atrial arrhythmias.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Aldosterone
  • Animals
  • Arrhythmias, Cardiac / chemically induced
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / metabolism*
  • Arrhythmias, Cardiac / physiopathology
  • Atrial Function, Left*
  • Atrial Remodeling*
  • Connexin 43 / metabolism
  • Disease Models, Animal
  • Heart Atria / metabolism*
  • Heart Atria / physiopathology
  • Heart Rate*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Sodium Chloride, Dietary
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*
  • Time Factors

Substances

  • Connexin 43
  • GJA1 protein, mouse
  • Sodium Chloride, Dietary
  • TRPM Cation Channels
  • TRPM4 protein, mouse
  • Aldosterone