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

Previous studies have shown that the activation of angiotensin II receptor type I (AT 1 ) 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, AT 1 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 AT 1 ‐calcineurin‐NFAT pathway. Here, we investigated the role of the AT 1 ‐calcineurin‐NFAT pathway in the remodeling of inward rectifier potassium (I k1 ) 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 NFAT 3 protein in nuclear extracts, the mRNA and protein expression of Kir2.1 in whole cell extracts, and the density of I k1 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 NFAT 3 , mRNA and protein expression of Kir2.1, the density of I k1 , and the APD. Our findings suggest that the AT 1 ‐calcineurin‐NFAT signaling pathway played an important role in regulating I k1 channel remodeling and APD change in stretch‐induced hypertrophic atrial myocytes of neonatal rats.