Received for publication April 21, 2008.
Revised July 22, 2008.
Accepted for publication July 22, 2008.

Sodium Hydrogen Exchange 1 (NHE-1) Regulates Connexin 43 Expression in Cardiomyocytes via Reverse Mode Sodium Calcium Exchange and JNK Dependent Pathways

Abstract

Connexin 43, the major connexin isoform in gap junctions of cardiac ventricular myocytes, undergoes changes in distribution and expression in cardiac diseases. The Na⁺-H⁺ exchanger (NHE-1), a key mediator of hypertrophy and heart failure has been shown to be localized in the cardiomyocyte gap junctional regions, however whether NHE-1 regulates gap junction proteins in the hypertrophied cardiomyocyte is not known. To address this question neonatal rat ventricular myocytes were treated with phenylephrine (PE) for 24 hours to induce hypertrophy. Increased Cx43 expression observed with PE treatment (132.4 ± 6.3 % compared to control; P<0.05) was further significantly augmented by the specific NHE-1 inhibitor EMD87580 (173.2 ± 8.7 % increase compared to control; P<0.05 vs PE), an effect which was mimicked by another NHE-1 inhibitor cariporide. PE-induced hypertrophy was associated with MAPK JNK1/2 activation whereas inhibition of JNK1/2 with either SP60015 or using siRNA significantly increased PE-induced upregulation of Cx43 protein levels. Inhibition of reverse mode Na⁺-Ca²⁺ exchange (NCX) with KB-R7943 partially reversed JNK1/2 activation (195.2 ± 21.4 % vs 143.7 ± 14.4 % with KB-R7943; P<0.05) and augmented upregulation of Cx43 protein (121.1 ± 8.3 % vs 215.9 ± 25.6 % with KB-R7943; P<0.05) in the presence of PE. Our results demonstrate that NHE-1 negatively regulates Cx43 protein expression in PE-induced cardiomyocyte hypertrophy via a JNK1/2 dependent pathway which is likely activated by reverse mode NCX activity.

Key words: JNK, Na-H exchange, cardiac myocytes, connexin 43, hypertrophy, reverse mode Na-Ca exchange