Enhanced Ca2+Channel Currents in Cardiac Hypertrophy Induced by Activation of Calcineurin-dependent Pathway

Cardiac-specific expression of an activated calcineurin protein in the hearts of transgenic (CLN) mice produces a profound hypertrophy that rapidly progresses to heart failure. While calcineurin is regulated by Ca2+, the potential effects of calcineurin on cardiac myocyte Ca2+handling has not been evaluated. To this end, we examined L-type Ca2+currents (ICa) in left ventricular myocytes. CLN myocytes had larger (≅80%) cell capacitance and enhanced ICadensity (≅20%) compared with non-transgenic (NTG) littermates, but no change in the current–voltage relationship, single-channel conductance or protein levels ofα 1 or β 2 subunit of L-type Ca2+channels. Interestingly, the kinetics of ICainactivation was faster (≅two-fold) in CLN myocytes compared with NTG myocytes. Ryanodine application slowed the rate of ICainactivation in both groups and abolished the kinetic difference, suggesting that Ca2+-dependent inactivation is increased in CLN myocytes due to altered SR Ca2+release. Treatment of CLN mice with Cyclosporine A (CsA), a calcineurin inhibitor, prevented myocyte hypertrophy and changes in ICaactivity and inactivation kinetics. However, there was no direct effect of CsA on ICain either NTG or CLN myocytes, suggesting that endogenous calcineurin activity does not directly regulate Ca2+channel activity. This interpretation is consistent with the observation that ICadensity, inactivation kinetics and regulation by isoproterenol were normal in cardiac-specific transgenic mice expressing calcineurin inhibitory protein domains from either Cain or AKAP79. Taken together these data suggest that chronic activation of calcineurin is associated with myocyte hypertrophy and a secondary enhancement of intracellular Ca2+handling that is tied to the hypertrophy response itself.