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 (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.

Prolonged duration of repolarization and decreased conduction velocity in the atrial myocardium after hypothermic ischemia-reperfusion may be related to expressions of inward rectifier potassium channel 2.1 protein and connexin 40

“…21,5 Kir2.1 protein is encoded by the KCNJ2 gene and is closely related to the duration of atrial repolarization. 22 The study of Lammers et al 23 revealed that expression of kir2.1 is inversely correlated with the duration of repolarization: the downregulation of kir2.1 protein expression prolonged the repolarization duration. Our results suggest that the duration of atrial repolarization in subgroup R-AA was significantly longer than that in group C and subgroup R-NAA.…”

Integrative computational modeling of calcium handling and cardiac arrhythmias

“…For example, activation of calcium/calcineurin/NFAT signaling increases IK1 through NFATmediated downregulation of the inhibitory microRNA-26 (173,225). IK1 was also increased in stretched neonatal rat atrial cardiomyocytes, which was also associated with augmented calcineurin activity and increased levels of nuclear NFAT3, as well as increased mRNA and protein expression of Kir2.1 (226). On the other hand, long-term β-adrenoceptor stimulation reduced IKs with a corresponding decrease in mRNA and protein expression of its β-subunit KCNE1.…”