GαQ/Gα11 Modulate Aldosterone Mediated Electrical Remodeling and Ca2+ Handling Alterations in Ventricular Myocytes

Abstract

Aldosterone stimulates unidirectional sodium transport across renal epithelial cells, thereby regulating blood volume and pressure. Clinical and experimental studies have linked hyperaldosteronism (HA) to diseases of the cardiovascular system. Although the involvement of Gq/G11 signaling in cardiac diseases has been hypothesized before, their contribution to HA-mediated cardiac remodeling is unknown. In this study we investigated the possible role of Gq/G11 in the electrical and Ca2+ homeostasis alterations induced by HA on ventricular myocytes. We generated heart specific inducible Gq/G11 KO-mice. In wt and KO mice HA was induced by implantation of osmotic minipumps. Serum levels of aldosterone were increased 7-fold in mice with aldosterone pumps when compared to animals receiving dummy pumps. To study cellular HA-mediated remodeling we isolated ventricular myocytes and subjected them patch-clamp investigations. In addition changes in global calcium handling were studied in fura2-loaded myocytes. All experiments were performed at 37°C. In wt animals with HA, we revealed massively altered action potentials characterized by a deformed repolarization that was shortened (APD30 & APD70). Interestingly, in cells from Gq/G11 dKO mice, HA did not alter the action potential. Concomitant with action potential shortening we found that Ito displayed a massively increased upregulation for HA-treated wt cells while in dKO myocytes Ito was normal. Global Ca2+ transient was also highly affected by HA in wt cells. Although these alterations were abolished in the first amplitude of Ca2+ transient, the post-rest behavior showed massive changes in HA-treated dKO cells. Hyperaldosteronism significantly altered the Ca2+ removal in both wt and Gq/G11 dKO, too.In conclusion our results demonstrate for the first time a direct involvement of Gq/G11 signaling in hyperaldosteronism-induced cardiac myocyte remodeling.This work was supported by the DFG, BMBF and the Medical Faculty.