Enhanced Ca2+Channel Currents in Cardiac Hypertrophy Induced by Activation of Calcineurin-dependent Pathway

Yatani, Atsuko; Honda, Ritsu; Tymitz, Kevin; Lalli, Jane M.; Molkentin, Jeffery D.

doi:10.1006/jmcc.2000.1296

Cited by 50 publications

(36 citation statements)

References 34 publications

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“…Here, we evaluated both cytoplasmic and mitochondrial insulin-dependent Ca 2+ signals in cardiomyocytes and assessed whether signaling is altered in hypertrophy. Deregulation of cytoplasmic Ca 2+ levels and changes in the expression of various Ca 2+ channels are hallmarks of cardiac hypertrophy [42][43][44]. However, with regards to cytoplasmic Ca 2+ signals induced by insulin we found no alterations in the shape, timing or intensity in hypertrophic cardiomyocytes.…”

Section: Mitochondrial Insulin-dependent Ca 2+ Signals In Hypertrophicontrasting

confidence: 51%

Alteration in mitochondrial Ca 2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes

Gutiérrez

Parra

Troncoso

et al. 2014

Cell Communication and Signaling

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Background: Cardiac hypertrophy is characterized by alterations in both cardiac bioenergetics and insulin sensitivity. Insulin promotes glucose uptake by cardiomyocytes and its use as a substrate for glycolysis and mitochondrial oxidation in order to maintain the high cardiac energy demands. Insulin stimulates Ca 2+ release from the endoplasmic reticulum, however, how this translates to changes in mitochondrial metabolism in either healthy or hypertrophic cardiomyocytes is not fully understood.

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Section: Mitochondrial Insulin-dependent Ca 2+ Signals In Hypertrophicontrasting

confidence: 51%

Alteration in mitochondrial Ca 2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes

Gutiérrez

Parra

Troncoso

et al. 2014

Cell Communication and Signaling

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“…Thus the effects of NO are dependent on the cellular environment including the presence of ␤ 1 versus ␤ 3 stimulation; cAMP, cGMP and phosphodiesterase activities; and the presence of congestive failure modulate responses. In a previous study (49), the overexpression of calcineurin increased I Ca, L activity; however, these studies were done early in the life of calcineurin mice (40). In the present study, the improvement in myocardial performance and dilation in iNOS Ϫ/Ϫ -CN/Tg myocytes may relate to improved calcium handling.…”

Section: Discussionmentioning

confidence: 44%

iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin

Somers

Beck²,

Lees‐Miller³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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HJ. iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin. Am J Physiol Heart Circ Physiol 295: H1122-H1131, 2008. First published July 11, 2008 doi:10.1152/ajpheart.00386.2008.-Transgenic overexpression of calcineurin (CN/Tg) in mouse cardiac myocytes results in hypertrophy followed by dilation, dysfunction, and sudden death. Nitric oxide (NO) produced via inducible NO synthase (iNOS) has been implicated in cardiac injury. Since calcineurin regulates iNOS expression, and since phenotypes of mice overexpressing iNOS are similar to CN/Tg, we hypothesized that iNOS is pathogenically involved in cardiac phenotypes of CN/Tg mice. CN/Tg mice had increased serum and cardiac iNOS levels. When CN/Tg-iNOS Ϫ/Ϫ and CN/Tg mice were compared, some phenotypes were similar: extent of hypertrophy and fibrosis. However, CN/Tg-iNOS Ϫ/Ϫ mice had improved systolic performance (P Ͻ 0.001) and less heart block (P Ͻ 0.0001); larger sodium current density and lower serum TNF-␣ levels (P Ͻ 0.03); and less apoptosis (P Ͻ 0.01) resulting in improved survival (P Ͻ 0.0003). To define tissue origins of iNOS production, chimeric lines were generated. Bone marrow (BM) from wild-type or iNOS Ϫ/Ϫ mice was transplanted into CN/Tg mice. iNOS deficiency restricted to BMderived cells was not protective. Calcineurin activates the local production of NO by iNOS in cardiac myocytes, which significantly contributes to sudden death, heart block, left ventricular dilation, and impaired systolic performance in this murine model of cardiac hypertrophy induced by the overexpression of calcineurin. heart block; sodium current; sudden death; inducible nitric oxide synthase; transgenic overexpression of calcineurin TRANSGENIC OVEREXPRESSION of constitutively active calcineurin (CN/Tg) in cardiac myocytes results in profound concentric hypertrophy followed by ventricular dilatation, interstitial fibrosis, heart failure, and eventually sudden cardiac death (13,26,32,33,40). The sudden deaths relate to ion channelopathies, which are downstream consequences of abnormalities of calcium homeostasis (17) and an inflammatory process (6, 10, 27, 36).Previous studies indicate that inducible nitric oxide (NO) synthase (iNOS) is a downstream target of calcineurin (12,19,36,44,45). The regulation of the iNOS gene promoter by calcineurin has been reported (36). LPS-induced iNOS expression in the heart was abrogated by the pharmacological inhibition of calcineurin (36). Similarly, LPS induced the expression of iNOS in wild-type (WT) hearts but not in the calcineurin A␤ knockout hearts (36). Reciprocally, the overexpression of constitutively active calcineurin in isolated cardiomyocytes caused the dephosphorylation and nuclear accumulation of the transcription factor family originally defined as nuclear factor of activated T-cells (NFAT)c1 and induced strong iNOS expression (36). In addition, chromatin immunoprecipitation confirmed the calcineurin-dependent binding of NFATc1 to the iNOS promoter (36). These data are co...

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“…In general, the current density of L-type Ca 2ϩ channels is either unchanged or slightly elevated when hypertrophy is mild and slightly reduced when hypertrophy is severe. [12][13][14] Although normally expressed during developmental stages and not expressed in adult cardiac myocytes, T-channels are 18,19,22 However, the physiological role of T-channel reexpression under these conditions is unclear.In this study, we aimed to determine whether Ca v 3.2 T-channels are involved in the development of pathological cardiac hypertrophy and whether the calcineurin-NFAT pathway is downstream of Ca v 3.2 T-channels during cardiac hypertrophy. Using Ca v 3.2 Ϫ/Ϫ and Ca v 3.1 Ϫ/Ϫ mice, we show that Ca v 3.2 but not Ca v 3.1 T-channels are required for the development of cardiac hypertrophy induced either by pressure overload and angiotensin (Ang) II treatment in vivo and in vitro.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Chiang

Huang

Chieng

et al. 2009

Circulation Research

145

123

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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 ...

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Enhanced Ca2+Channel Currents in Cardiac Hypertrophy Induced by Activation of Calcineurin-dependent Pathway

Cited by 50 publications

References 34 publications

Alteration in mitochondrial Ca 2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes

Alteration in mitochondrial Ca 2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes

iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin

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

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Enhanced Ca2+Channel Currents in Cardiac Hypertrophy Induced by Activation of Calcineurin-dependent Pathway

Cited by 50 publications

References 34 publications

Alteration in mitochondrial Ca 2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes

Alteration in mitochondrial Ca 2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes

iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin

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

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