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 hart 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 (I-Ca) in left ventricular myocytes. CLN myocytes had larger (approximate to 80%) cell capacitance and enhanced I-Ca density (approximate to 20%) compared with non-transgenic (NTG) littermates, but no change in the current-voltage relationship, single-channel conductance or protein levels of alpha1 or beta2 subunit of L-type Ca2+ channels. Interestingly, the kinetics of I-Ca inactivation was faster (approximate to two-fold) in CLN myocytes compared with NTG myocytes. Ryanodine application slowed the rate of I-Ca inactivation 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 I-Ca activity and inactivation kinetics. However, there was no direct effect of CsA on I-Ca in 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 I-Ca density, 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. (C) 2001 Academic Press.