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(Circulation Research. 2009;104:522.)
© 2009 American Heart Association, Inc.

Cellular Biology

The Ca_V3.2 T-Type Ca²⁺ Channel Is Required for Pressure Overload–Induced Cardiac Hypertrophy in Mice

Chien-Sung Chiang^*, Ching-Hui Huang^*, Hockling Chieng, Ya-Ting Chang, Dory Chang, Ji-Jr Chen, Yong-Cyuan Chen, Yen-Hui Chen, Hee-Sup Shin, Kevin P. Campbell, Chien-Chang Chen

From the Institute of Biomedical Sciences (C.-S.C., C.-H.H., H.C., Y.-T.C., D.C., J.-J.C., Y.-C.C.,Y.-H.C., C.-C.C.), Academia Sinica, Taipei, Taiwan; Graduate Institute of Life Sciences (C.-H.H., C.-C.C.), National Defense Medical Center, Taipei, Taiwan; Center for Neural Science (H.-S.S.), Korea Institute of Science and Technology, Seoul, Korea; and Department of Physiology and Biophysics and Department of Neurology (K.P.C.), Howard Hughes Medical Institute, University of Iowa, Iowa City.

Correspondence to Chien-Chang Chen, Institute of Biomedical Sciences, Academia Sinica, 128 Academia Rd Sec 2, Nankang, Taipei 11529, Taiwan. E-mail ccchen{at}ibms.sinica.edu.tw

Voltage-gated T-type Ca²⁺ 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 Ca²⁺ channel (Ca_v3.2) 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 Ca_v3.2 (Ca_v3.2^–/–) but not in mice deficient for Ca_v3.1 (Ca_v3.1^–/–). Angiotensin II–induced cardiac hypertrophy was also suppressed in Ca_v3.2^–/– mice. Consistent with these findings, cultured neonatal myocytes isolated from Ca_v3.2^–/– mice fail to respond hypertrophic stimulation by treatment with angiotensin II. Together, these results demonstrate the importance of Ca_v3.2 in the development of cardiac hypertrophy both in vitro and in vivo. To test whether Ca_v3.2 mediates the hypertrophic response through the calcineurin/NFAT pathway, we generated Ca_v3.2^–/–, NFAT-luciferase reporter mice and showed that NFAT-luciferase reporter activity failed to increase after pressure overload in the Ca_v3.2^–/–/NFAT-Luc mice. Our results provide strong genetic evidence that Ca_v3.2 indeed plays a pivotal role in the induction of calcineurin/NFAT hypertrophic signaling and is crucial for the activation of pathological cardiac hypertrophy.

Key Words: hypertrophy • cardiomyopathy • T-type Ca²⁺ channel

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