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

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