Ca(2+) signaling domains responsible for cardiac hypertrophy and arrhythmias.

Ca 2 activates and regulates multiple processes in every cell type. In the mammalian heart, cyclic fluctuations in cytosolic [Ca ] induce and regulate the strength of cardiac contraction (termed “contractile” [Ca ]). In addition, changes in Ca appear to be centrally involved in normal and pathological signaling (termed “signaling” [Ca ]) that regulates myocyte growth, hypertrophy, apoptosis, and necrosis.1 Whether or not contractile and signaling [Ca ] are derived from common or distinct sources and are constrained to unique cellular microdomains is not established.2 What is clear is that cardiovascular diseases including hypertension and myocardial infarction are associated with alterations in contractile and possibly signaling [Ca ] that are centrally involved in pathological cardiac hypertrophy, heart failure progression,1 and lethal cardiac arrhythmias.3 Defining the sources of signaling Ca involved in the induction of pathological hypertrophy and the bases of dysregulated contractile [Ca ] in cardiovascular disease should identify novel ways to treat heart disease. In this issue of Circulation Research, 2 independent reports address fundamental aspects of alterations in signaling and contractile [Ca ]. Chiang et al4 have studied the idea that Ca influx through voltage operated 1H (CaV3.2) T-type Ca channels (TTCCs) is the source of the signaling [Ca ] that activates the calcineurin (Cn)-NFAT (nuclear factor of activated T cells) signaling cascade and induces pathological cardiac hypertrophy in pressure overload. In a separate report, Terentyev et al5 explore the idea that microRNA (miR)-1, a muscle-specific microRNA that increases in abundance in cardiac disease,6 causes dysregulated contractile [Ca ] and induces single cell arrhythmias. These 2 reports are provocative and, if independently confirmed, will have identified novel mechanisms for abnormalities in the signaling and contractile [Ca ] that cause hypertrophy and sudden death. Almost 20 years ago, we7 and others8 showed that TTCCs are reexpressed in adult ventricular myocytes after pressure overload. TTCCs are expressed in fetal/neonatal heart but are not normally found in the adult ventricular myocyte. We speculated that the Ca influx through these channels was involved in the induced cardiac hypertrophy.7 The report by Chiang et al4 explores this idea in TTCC knockout (KO) mouse models. There are 3 TTCC genes, and 2 ( 1G [CaV3.1] and 1H [CaV3.2]) are found in the heart.9 CaV3.1 and 3.2 KO11 animals, each of which is viable with modest basal phenotypes,10,11 were used. The authors make the provocative observation that thoracic aortic constriction (TAC) induces cardiac hypertrophy in the CaV3.1 KO and control animals, but not in CaV3.2 KO. CaV3.2 KO animals had similar degrees of pressure overload after TAC, documenting a similar degree of stress. The inability of TAC to induce hypertrophy in CaV3.2 KO appeared to be attributable to the fact that Cn-mediated nuclear NFAT translocation, which is known to induce pathological hypertrophy,12 was not activated in these animals. Surprisingly, the fetal gene program activated with pathological hypertrophy was induced by TAC in CaV3.2 KO without left ventricular hypertrophy. These are provocative results that, if confirmed, will change thinking in the field. These results suggest that most if not all of NFAT mediated pathological hypertrophy is induced by a very small influx of Ca through reexpressed 1H TTCCs. These new findings also suggest that Cn-NFAT signaling is not influenced by changes in the amplitude and duration of the systolic [Ca ] transient (contractile [Ca ]). Contractility in CaV3.2 KO mice after TAC must be greater than in controls which develop left ventricular hypertrophy, because CaV3.2 KO hearts are generating high pressures with less cardiac mass. Therefore, the systolic Ca must be greater in CaV3.2 KO TAC myocytes than in control TAC hearts, yet there was no activation of Cn-NFAT signaling. These results are different from those that have linked the activation of Cn-NFAT signaling with increases in either the rate or amplitude of the cytoplasmic (contractile) [Ca ] transient in skeletal13 and cardiac muscle.2,14 The report by Chiang et al4 also suggests that Ca activated Cn-NFAT signaling does not play a role in the activation of the fetal gene program after TAC. Their studies show no activation of Cn-NFAT signaling in CaV3.2 KO animals after TAC, but the fetal gene program was induced. In fact, the induction was greater than in controls after TAC. These results suggest that NFAT nuclear translocation has no role in the activation of these well studied fetal genes. Such results are in stark contract to studies that have shown equally convincing data documenting that block of NFAT nuclear translocation eliminates agonist and pressure overload induced hypertrophy and the activation of the fetal gene program.12 Because these data sets seem mutually exclusive this topic clearly needs additional study. The provocative study by Chiang et al4 suggests that pressure overload causes hypertrophy by inducing the expression of CaV3.2 TTCCs. A very small Ca 2 influx through these channels would need to enter a specialized subsarThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Temple University School of Medicine, Philadelphia, Pa. Correspondence to Steven R. Houser, PhD, FAHA, Laura H. Carnell Professor of Physiology, Temple University School of Medicine, 3400 N Broad St, Philadelphia, PA 19140. E-mail [email protected] (Circ Res. 2009;104:413-415.) © 2009 American Heart Association, Inc.