The Ca _V 3.2 T-Type Ca ²⁺ Channel Is Required for Pressure Overload–Induced Cardiac Hypertrophy in Mice

Abstract

Abstract-Voltage-gated T-type Ca 2ϩ 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 2ϩ channel (Ca v 3.2) 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 v 3.2 (Ca v 3.2 Ϫ/Ϫ ) but not in mice deficient for Ca v 3.1 (Ca v 3.1 Ϫ/Ϫ ). Angiotensin II-induced cardiac hypertrophy was also suppressed in Ca v 3.2 Ϫ/Ϫ mice. Consistent with these findings, cultured neonatal myocytes isolated from Ca v 3.2 Ϫ/Ϫ mice fail to respond hypertrophic stimulation by treatment with angiotensin II. Together, these results demonstrate the importance of Ca v 3.2 in the development of cardiac hypertrophy both in vitro and in vivo. To test whether Ca v 3.2 mediates the hypertrophic response through the calcineurin/NFAT pathway, we generated Ca v 3.2 Ϫ/Ϫ , NFAT-luciferase reporter mice and showed that NFAT-luciferase reporter activity failed to increase after pressure overload in the Ca v 3.2 Ϫ/Ϫ /NFAT-Luc mice. Our results provide strong genetic evidence that Ca v 3.2 indeed plays a pivotal role in the induction of calcineurin/NFAT hypertrophic signaling and is crucial for the activation of pathological cardiac hypertrophy. H ypertrophic growth and remodeling of the adult heart begin as normal compensatory responses to a variety of physiological and pathological stimuli including exercise, pregnancy, pressure overload, hypertension, myocardial infarction, and primary genetic abnormalities. [1][2][3] Prolonged hypertrophic response may eventually lead to heart failure and death. Pathological hypertrophy is often associated with structural and functional remodeling of the heart. Profound changes in gene expression during pathological cardiac hypertrophy are common, particularly in the case of genes that code for proteins involved in regulating contraction ion channels, for example. 4 Alterations of intracellular Ca 2ϩ handling could lead to abnormal Ca 2ϩ signaling cascades, a phenomenon that has been shown to contribute to the pathogenesis of cardiac hypertrophy and heart failure. 5,6 However, the detailed mechanism of how the cardiac myocytes distinguish Ca 2ϩ transients that occur at every heartbeat from those meant to trigger intracellular hypertrophic signaling remains largely unknown. Intracellular Ca 2ϩ levels could be altered because of either changes in Ca 2ϩ release from intracellular organelles or the influx of extracellular Ca 2ϩ , and in both cases, this could be attributable to the activities of either ligand-or voltage-activated Ca 2ϩ channels. Indeed, ligand-activated Ca 2ϩ channels, such as ...

Self-beating Atypically Shaped Cardiomyocytes Survive a Long-term Postnatal Development While Preserving the Expression of Fetal Cardiac Genes in Mice

“…Ca V 3.2 is also preferentially expressed in fetal ventricles, but less so in adult ventricles, and therefore the T-type Ca 21 current is very small or even undetectable in adult ventricular myocytes (Perez-Reyes 2003;Chiang et al 2009). ACMs from both day-1 (Figures 6A-6C) and aged ( Figures 6D-6F) hearts also expressed Ca V 3.2 predominantly in the intracellular space rather than the cell periphery, whereas very weak signals were detected near the plasma membrane in adult cardiac ventricular myocytes ( Figures 6G-6I).…”

Pathophysiological Remodeling of Mouse Cardiac Myocytes Expressing Dominant Negative Mutant of Neuron Restrictive Silencing Factor

“…23 It has been recently reported that CaV3.2 (Cacna1h) is required for cardiac hypertrophy induced by pressure overload. 24 Likewise, crossbreeding of dnNRSF mice with transgenic mice lacking the target genes of REST/NRSF might provide a clue.…”

T-type Ca2+channels and autoregulation of local blood flow

“…However, Ca V 3.1 and Ca V 3.2 channels are also expressed in the heart where they are involved in pacemaking in the sinoatrial node (Ca V 3.1; 43 ) as well as in ventricular hypertrophy where Ca V 3.1 and Ca V 3.2 channels seem to play opposite roles. 44,45 Moreover, in resistance vessels Ca V 3.1 and Ca V 3.2 T-type channel protein expression has been demonstrated by immunolocalization to VSMCs 46-51 as well as ECs. 48,49,51,52 Interestingly, in human cerebral arteries the T-type isoforms expressed are the Ca V 3.2 and Ca V 3.3 channels, with no expression of Ca V 3.1 channels.…”