Channel Is Required for Pressure Overload–Induced Cardiac Hypertrophy in Mice

Voltage-gated T-type Ca channels (T-channels) are normally expressed during embryonic development in ventricular myocytes but are undetectable in adult ventricular myocytes. Interestingly, T-channels are reexpressed in hypertrophied or failing hearts. It is unclear whether T-channels play a role in the pathogenesis of cardiomyopathy and what the mechanism might be. Here we show that the 1H voltage-gated T-type Ca 2 channel (Cav3.2) is involved in the pathogenesis of cardiac hypertrophy via the activation of calcineurin/nuclear factor of activated T cells (NFAT) pathway. Specifically, pressure overload–induced hypertrophy was severely suppressed in mice deficient for Cav3.2 (Cav3.2 / ) but not in mice deficient for Cav3.1 (Cav3.1 / ). Angiotensin II–induced cardiac hypertrophy was also suppressed in Cav3.2 / mice. Consistent with these findings, cultured neonatal myocytes isolated from Cav3.2 / mice fail to respond hypertrophic stimulation by treatment with angiotensin II. Together, these results demonstrate the importance of Cav3.2 in the development of cardiac hypertrophy both in vitro and in vivo. To test whether Cav3.2 mediates the hypertrophic response through the calcineurin/NFAT pathway, we generated Cav3.2 / , NFAT-luciferase reporter mice and showed that NFAT-luciferase reporter activity failed to increase after pressure overload in the Cav3.2 / /NFAT-Luc mice. Our results provide strong genetic evidence that Cav3.2 indeed plays a pivotal role in the induction of calcineurin/NFAT hypertrophic signaling and is crucial for the activation of pathological cardiac hypertrophy. (Circ Res. 2009;104:522-530.)