A Ca
            <sup>2+</sup>
            -Dependent Transgenic Model of Cardiac Hypertrophy

Muth, James N.; Bódi, Ilona; Lewis, William; Váradi, Gyula; Schwartz, Arnold

doi:10.1161/01.cir.103.1.140

Cited by 143 publications

(79 citation statements)

References 32 publications

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“…Increased Ca 2+ influx via Ca V 1.2 channels in cardiomyocytes has been proposed to be responsible for cardiac hypertrophy and pathological remodeling of the ventricles in both animal models and human patients (27,28,(37)(38)(39). In keeping with these results, overexpression of Ca V 1.2 channels in the hearts of transgenic mice leads to cardiac hypertrophy and heart failure (40). Moreover, Ca V 1.2 blockers effectively inhibit cardiac remodeling and prevent cardiomyopathy in animal models with pressure overload (41,42).…”

Section: Discussionmentioning

confidence: 83%

“…Second, we demonstrate that up-regulation of PKA expression is potentially a key link in Ca V 1.2 channel dysfunction, cardiac hypertrophy, and heart failure. Because calcineurin/NFAT signaling is engaged to cause cardiac hypertrophy induced by increased Ca V 1.2 protein expression (32,40), decreased Ca V 1.2 protein expression (43), and impaired regulation of Ca V 1.2 (this work), this mechanism gains increased emphasis as a common pathway leading to hypertrophy and heart failure.…”

Section: Sa Mice Show Increased Cardiovascular Pathology In Response Tomentioning

confidence: 99%

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Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Yang

Dai

Yuan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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L-type Ca 2+ currents conducted by voltage-gated calcium channel 1.2 (Ca V 1.2) initiate excitation-contraction coupling in the heart, and altered expression of Ca V 1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of Ca V 1.2 channels by mutation of a single PKA site, Ser1700, in the proximal C-terminal domain causes reduced contractile function, cardiac hypertrophy, and heart failure without changes in expression, localization, or function of the Ca V 1.2 protein in the mutant mice (SA mice). These deficits were aggravated with aging. Dual mutation of Ser1700 and a nearby casein-kinase II site (Thr1704) caused accelerated hypertrophy, heart failure, and death in mice with these mutations (STAA mice). Cardiac hypertrophy was increased by voluntary exercise and by persistent β-adrenergic stimulation. PKA expression was increased, and PKA sites Ser2808 in ryanodine receptor type-2, Ser16 in phospholamban, and Ser23/24 in troponin-I were hyperphosphorylated in SA mice, whereas phosphorylation of substrates for calcium/calmodulin-dependent protein kinase II was unchanged. The Ca 2+ pool in the sarcoplasmic reticulum was increased, the activity of calcineurin was elevated, and calcineurin inhibitors improved contractility and ameliorated cardiac hypertrophy. Cardio-specific expression of the SA mutation also caused reduced contractility and hypertrophy. These results suggest engagement of compensatory mechanisms, which initially may enhance the contractility of individual myocytes but eventually contribute to an increased sensitivity to cardiovascular stress and to heart failure in vivo. Our results demonstrate that normal regulation of Ca V 1.2 channels by phosphorylation of Ser1700 in cardiomyocytes is required for cardiovascular homeostasis and normal physiological regulation in vivo.calcium channel | heart failure | excitation-contraction coupling | PKA | casein kinase II E xcitation-contraction (EC) coupling in the heart is initiated by L-type calcium (Ca 2+ ) currents conducted by voltagegated calcium 1.2 (Ca V 1.2) channels that are activated by membrane depolarization (1). Ca 2+ influx via Ca V 1.2 channels activates Ca 2+ release from the sarcoplasmic reticulum (SR), leading to rapid and forceful contraction of myofilaments. Ryanodine receptor type-2 (RyR2) is the major channel for this release of Ca 2+ from cardiac SR (2, 3). Mobilized Ca 2+ is transported back into the SR by the SR Ca 2+ ATPase (SERCA) during muscle relaxation (4). SERCA activity is controlled by the inhibitor protein phospholamban (PLB), which is phosphorylated by PKA to release its inhibition of SERCA activity (4). The force and rate of cardiac contractions are critically dependent on the amplitude and kinetics of the Ca 2+ signal generated by Ca V 1.2 channels and RyR2 (1). In the fight-or-flight response, a marked increase in the beating rate and force of contraction of the heart is triggered by activation of the sympathetic nervous system and stimulation of the β-adrenergic signaling p...

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Section: Discussionmentioning

confidence: 83%

Section: Sa Mice Show Increased Cardiovascular Pathology In Response Tomentioning

confidence: 99%

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Yang

Dai

Yuan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…PKC␣, the most predominant PKC isoform in the heart, is sufficient to promote cardiac hypertrophy when overexpressed in neonatal rat cardiac myocytes (4). PKC␣ activation has also been shown to precede hypertrophy in a mouse model of L-type voltage-dependent calcium channel overexpression (36). Recently, it was shown that cardiac function was maintained in PKC␣-null mice following aortic banding, a surgical model of pressure overload induced heart failure (5).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5

Vega

Harrison²,

Meadows

et al. 2004

Molecular and Cellular Biology

481

514

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A variety of stress signals stimulate cardiac myocytes to undergo hypertrophy. Persistent cardiac hypertrophy is associated with elevated risk for the development of heart failure. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy and that stress signals neutralize this repressive function by triggering phosphorylation-and CRM1-dependent nuclear export of these chromatin-modifying enzymes. However, the identities of cardiac HDAC kinases have remained unclear. Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. Inhibition of PKC prevents nucleocytoplasmic shuttling of HDAC5 in response to a subset of hypertrophic agonists. Moreover, a nonphosphorylatable HDAC5 mutant is refractory to PKC signaling and blocks cardiomyocyte hypertrophy mediated by pharmacological activators of PKC. We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. These findings reveal a novel function for the PKC/PKD axis in coupling extracellular cues to chromatin modifications that control cellular growth, and they suggest potential utility for small-molecule inhibitors of this pathway in the treatment of pathological cardiac gene expression.Coordinated changes in gene transcription during cell growth and differentiation require mechanisms for coupling intracellular signaling pathways with the genome. The acetylation of nucleosomal histones has emerged as a central mechanism in the control of gene transcription during such cellular transitions (20). Acetylation of histones by histone acetyltransferases promotes transcription by relaxing chromatin structure, whereas histone deacetylation by histone deacetylases (HDACs) reverses this process, resulting in transcriptional repression. How these chromatin-modifying enzymes are linked to, and controlled by, intracellular signaling is only beginning to be understood.There are two classes of HDACs that can be distinguished by their structures and expression patterns. Class I HDACs (HDAC1, HDAC2, and HDAC3) are expressed ubiquitously and are composed mainly of a catalytic domain (13). In contrast, class II HDACs (HDAC4, HDAC5, HDAC7, and HDAC9) display more restricted expression patterns and contain an N-terminal extension, which mediates interactions with other transcriptional cofactors and confers responsiveness to calcium-dependent signaling (12,25,33). Signaling by calcium/ calmodulin-dependent protein kinase (CaMK) results in phosphorylation of the N termini of class II HDACs, which govern their intracellular localization and interactions with other factors (29, 32). Phosphorylation of signal-responsive serine residues creates docking sites for the 14-3-3 family of chaperone proteins, which promote shuttling of HDACs from the nucleus to the cytoplasm in a CRM1-dependent fashion (14,21,30,31,48).CaMK signaling to class II HDACs governs the activity of th...

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“…Taken together, our results show that electrical remodeling precedes cellular hypertrophy, independently of the so-called mechanoconversion, 1 and might be one of the primary factors. 14,17,32 In this regard, calcineurin, which triggers the hypertrophic response, 33 is a Ca 2ϩ -dependent phosphatase. Hence, an increase in Ca 2ϩ signaling must precede calcineurin activation to initiate hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

“…15,16 Moreover, ionic remodeling might be a primary factor in triggering cardiac hypertrophy. 17 Accordingly, electrical remodeling could be independent of mechanical overload, and a specific signal must initiate the remodeling.…”

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confidence: 99%

Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction

et al. 2004

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Background-Cardiac hypertrophy underlies arrhythmias and sudden death, for which mineralocorticoid receptor (MR) activity has recently been implicated. We sought to establish the sequence of ionic events that link the initiating insult and MR to hypertrophy development. Methods and Results-Using whole-cell, patch-clamp and quantitative reverse transcription-polymerase chain reaction techniques on right ventricular myocytes of a myocardial infarction (MI) rat model, we examined the cellular response over time. One week after MI, no sign of cellular hypertrophy was found, but action potential duration (APD) was lengthened. Both an increase in Ca 2ϩ current (I Ca ) and a decrease in K ϩ transient outward current (I to ) underlay this effect. Consistently, the relative expression of mRNA coding for the Ca 2ϩ channel ␣1C subunit (Ca v 1.2) increased, and that of the K ϩ channel K v 4.2 subunit decreased. Three weeks after MI, AP prolongation endured, whereas cellular hypertrophy developed. I Ca density, Ca v 1.2, and K v 4.2 mRNA levels regained control levels, but I to density remained reduced. Long-term treatment with RU28318, an MR antagonist, prevented this electrical remodeling. In a different etiologic model of abdominal aortic constriction, we confirmed that APD prolongation and modifications of ionic currents precede cellular hypertrophy. Conclusions-Electrical remodeling, which is triggered at least in part by MR activation, is an initial, early cellular response to hypertrophic insults.

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A Ca ²⁺ -Dependent Transgenic Model of Cardiac Hypertrophy

Cited by 143 publications

References 32 publications

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5

Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction

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A Ca 2+ -Dependent Transgenic Model of Cardiac Hypertrophy

Cited by 143 publications

References 32 publications

Loss of β-adrenergic–stimulated phosphorylation of Ca V 1.2 channels on Ser1700 leads to heart failure

Loss of β-adrenergic–stimulated phosphorylation of Ca V 1.2 channels on Ser1700 leads to heart failure

Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5

Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction

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Product

Resources

About

A Ca ²⁺ -Dependent Transgenic Model of Cardiac Hypertrophy

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure