Cyclosporin Inhibits Cardiomegaly in the Conditional, Cardiac GCaMP2 Mice

Abstract

Mice expressing the Ca2+ sensor protein GCaMP2 in cardiac myocytes under the control of a doxocycline -regulated αMHC promoter (ccGC2 mice) develop cardiomegaly by 14 weeks. As the transgene consists of a calmodulin – eGFP chimeric protein, we performed initial experiments to examine the mechanism(s) underlying the development of cardiac hypertrophy. Previous observations suggest that the overexpression of calmodulin can lead to hypertrophic cardiomyopathy (Gruver et al Endocrin 1993), suggesting a possible activation of the calcineurin/nFAT pathway (Dong et al Cardio Res 2003, Molkentin et al Cell 1998). We examined whether inhibiting the activation of this pathway prevented GCaMP2 dependent development of cardiac hypertrophy. Beginning at post natal day 7, wildtype and ccGC2 litter mate controls were injected with either vehicle only or cyclosporin (10–20mg/kg) twice daily for two weeks. Mice were euthanized at 3 weeks of age, at which time heart and body weight were measured. The heart to body weight ratio in 3 week old ccGC2 mice injected with vehicle was 15% greater than vehicle injected wildtype mice or ccGC2 mice injected with cyclosporin A (5.8 ± 0.2 n=5; 5.1 ± 0.2 n=5; 5.2 ± 0.1 n=7 p < 0.02, respectively). Cardiomegaly was inhibited in ccGC2 mice injected with cyclosporin A when compared to cyclosporin A injected wildtype litter mate controls (5.2 ± 0.1 n=7; 5.3 ± 0.1 n=6, respectively). These data suggest that GCaMP2 transgene expression produces cardiac hypertrophy through stimulation of of calcineurin pathway. As the transgene is temporally regulated, ccGC2 mice may be useful in examining the signaling processes leading to the development of cardiomegaly in adult mice. Values are ± SE. NIH grants HL45239 and DK58795.