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 (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.

Crim1 inhibits angiotensin II-induced hypertrophy and preserves Kv4.2 expression in cardiomyocytes.

Objectives: Angiotensin II (Ang II) plays a key role in the regulation of myocardial hypertrophy via downstream cysteine-rich transmembrane bone morphogenetic protein regulator 1 (Crim1). However, it is still unclear whether Crim1 is involved in ionic channel remodeling. The study aimed to explore the effects of Crim1 on transient outward potassium current (Ito) and Kv4.2 (the main subunit of Ito channel) expression in hypertrophic ventricular cardiomyocytes. Materials and Methods: The ventricular cardiomyocytes were isolated from the neonatal rats. Hypertrophy was induced by Ang II. Crim1 expression was modulated by using adenovirus transfection. The expression of myosin heavy chain beta (ß-MHC), Crim1, and Kv4.2 was determined by RT-qPCR and western blot. The cellular surface area was assessed using Image J software. Ito was recorded by the whole-cell patch clamp technique. Results: Ang II-induced hypertrophy in cardiomyocytes was identified by their larger cellular surface area and higher mRNA expression of ß-MHC. Ang II significantly decreased the expression of Crim1 and Kv4.2 and reduced Ito current density. However, Crim1 overexpression abolished the Ang II-induced hypertrophy and preserved the expression of Kv4.2 and Ito current density. Conclusion: Crim1 overexpression inhibits Ang II-induced hypertrophy and preserves Ito current density via up-regulating Kv4.2 in ventricular cardiomyocytes from neonatal rats. Crim1 could have a role in the development of ventricular arrhythmia in hypertrophic hearts.

Calcineurin Aß gene knockdown inhibits transient outward potassium current ion channel remodeling in hypertrophic ventricular myocyte.

It has been shown that the activation of calcineurin is involved in regulating ion channel remodeling in hypertrophic cardiomyocytes. But the precise role of calcineurin in the regulation of transient outward potassium current (I to), an ion channel associated with fatal arrhythmia, remains controversial. This study aimed to examine the effects of calcineurin Aß (CnAß) gene knockdown on I to channel remodeling and action potential duration (APD) in the hypertrophic ventricular myocytes of neonatal rats. Results showed that phenylephrine stimulation caused hypertrophy of ventricular myocytes, upregulation of CnAß protein expression, downregulation of Kv4.2 mRNA and protein expression, a decrease in I to current density, and prolongation of APD. CnAß gene knockdown significantly inhibited the effects of phenylephrine stimulation. Our data indicate that CnAß gene knockdown can inhibit I to channel remodeling and APD prolongation in hypertrophic neonatal rat ventricular myocytes. This finding suggests that calcineurin may be a potential target for the prevention of malignant ventricular arrhythmia in a hypertrophic heart.

Crim1 suppresses left ventricular hypertrophy.

Left ventricular hypertrophy is a leading cause of heart failure and sudden death. Cysteine-rich transmembrane bone morphogenetic protein regulator 1 (Crim1) is expressed at a high level in the heart and has a regulatory role in heart development. The present study aimed to test the hypothesis that Crim1 can have an inhibitory function on ventricular hypertrophy. Rat primary ventricular myocytes were stretched to induce myocyte hypertrophy, and treated with telmisartan or infected with Crim1-expressing recombinant adenovirus (Ad-Crim1). Rat ventricular hypertrophy was induced by abdominal aortic coarctation (AAC), and treated either with telmisartan or myocardial injection of Ad-Crim1 or empty adenovirus vector. The results showed that the expression of Crim1 decreased in the hypertrophic ventricle. The inhibition of angiotensin receptor type 1 (AT1R) by telmisartan in vitro and in vivo significantly increased the expression of Crim1 in the left ventricle. The overexpression of Crim1 by infection with Ad-Crim1 significantly inhibited stretch-induced ventricular myocyte hypertrophy in vitro. The overexpression of Crim1 by gavage with AT1R inhibitor telmisartan or myocardial injection of Ad-Crim1 markedly suppressed AAC-induced left ventricular hypertrophy in vivo. These results suggest that Crim1 has a suppressive function on ventricular hypertrophy and provides a novel therapeutic target for the treatment of cardiac hypertrophy.

Erratum: Crim1 suppresses left ventricular hypertrophy.

[This corrects the article DOI: 10.3892/br.2019.1214.].