Regulation of inward rectifier potassium current ionic channel remodeling by AT1 -Calcineurin-NFAT signaling pathway in stretch-induced hypertrophic atrial myocytes.

Abstract

Previous studies have shown that the activation of angiotensin II receptor type I (AT1 ) is attributed to cardiac remodeling stimulated by increased heart load, and that it is followed by the activation of the calcineurin-nuclear factor of activated T-cells (NFAT) signaling pathway. Additionally, AT1 has been found to be a regulator of cardiocyte ionic channel remodeling, and calcineurin-NFAT signals participate in the regulation of cardiocyte ionic channel expression. A hypothesis therefore follows that stretch stimulation may regulate cardiocyte ionic channel remodeling by activating the AT1 -calcineurin-NFAT pathway. Here, we investigated the role of the AT1 -calcineurin-NFAT pathway in the remodeling of inward rectifier potassium (Ik1 ) channel, in addition to its role in changing action potential, in stretch-induced hypertrophic atrial myocytes of neonatal rats. Our results showed that increased stretch significantly led to atrial myocytes hypertrophy; it also increased the activity of calcineurin enzymatic activity, which was subsequently attenuated by telmisartan or cyclosporine-A. The level of NFAT3 protein in nuclear extracts, the mRNA and protein expression of Kir2.1 in whole cell extracts, and the density of Ik1 were noticeably increased in stretched samples. Stretch stimulation significantly shortened the action potential duration (APD) of repolarization at the 50% and 90% level. Telmisartan, cyclosporine-A, and 11R-VIVIT attenuated stretch-induced alterations in the levels of NFAT3 , mRNA and protein expression of Kir2.1, the density of Ik1 , and the APD. Our findings suggest that the AT1 -calcineurin-NFAT signaling pathway played an important role in regulating Ik1 channel remodeling and APD change in stretch-induced hypertrophic atrial myocytes of neonatal rats.