Cell volume-regulated ion channels and ionic remodeling in hypertrophied mouse heart

Abstract

In the adaptive response to myocardial hypertrophy and heart failure, cell volume changes may cause ionic channel remodeling in the heart and thus produces substrates for cardiac arrhythmias and contraction disorders. The predominant pathway for cell volume homeostasis is the regulation of separate Cl− and K+ channel activities. To study the functional role of Cl− and K+ channels in the myocardial hypertrophy and heart failure, we developed a pressure overload model through a minimally invasive transverse aortic banding (MTAB) at the level of suprasternal notch in age-matched wild-type (WT) and gene-engineered mice. Changes in cardiac function of the animals before and after MTAB were monitored using echocardiography every week after the surgery. Changes in cardiac hemodynamics, heart weight, and histology were examined in mice of the 1st, 5th, and 10th week after MTAB. In comparison with the WT mice, ClC-3 knockout (ClCn3−/−) mice developed myocardial hypertrophy significantly faster (<1 week vs >4 weeks to reach the peak of increase in wall thickness). While the hypertrophied changes maintained at a similar level for >10 weeks after MTAB in WT mice, dilated changes (decrease in wall thickness and increase in chamber dimensions) and decrease in heart function were observed in ClCn3−/− mice after 6 weeks of MTAB. These results suggest that activation of ClC-3 channels may be important in the adaptive remodeling of the heart during pressure overload. Targeted deactivation of ClC-3 gene, which is responsible for the cell swelling-induced Cl− current (ICl.swell) in mouse heart causes an acceleration of the progression of heart failure during MTAB. We also found that the transient outward K+ current (Ito) carried by Kv4.2 and KV4.3 channels in the mouse heart is also regulated by cell volume changes in a similar manner to the regulation of ICl.swell and is tightly coupled to PKC phosphorylation/dephosphorylation of the channel. In MTAB-induced hypertrophied mouse heart, there was a substantial decrease in the Ito current density and Kv4.2/Kv4.3 channel protein expression. These findings suggest that volume regulated ion channels may play an important role in myocardial hypertrophy and congestive heart failure. Since cell volume regulation has a critical impact on cell proliferation and apoptosis, it is conceivable that volume-regulated ion channels may play crucial roles in the remodeling process of the heart and may represent very attractive novel targets for therapeutic approaches to the treatment of heart failure.