Pressure Overload Selectively Up-Regulates Ca<sup>2+</sup>/Calmodulin-Dependent Protein Kinase II<i>in Vivo</i>

Colomer, Josep M.; Rockman, Howard A.; Means, Anthony R.

doi:10.1210/me.2002-0350

Cited by 88 publications

(79 citation statements)

References 48 publications

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“…Our results show that the loss of CaMKII␦ attenuates fetal gene activation and pathological cardiac remodeling in response to pressure overload without affecting general Ca 2ϩ handling. Prior studies showed that CaMKII␦ and CaMKII␥ are activated in response to pressure overload (26). CaMKII␤ is also expressed at a low level in the heart (35).…”

Section: Discussionmentioning

confidence: 99%

“…CaMKII␦ expression and activity are up-regulated in structural heart disease (25,26), and transgenic overexpression of the nuclear splice variant CaMKII␦B (27) or the cytosolic splice variant CaMKII␦C (28) promotes cardiac hypertrophy. Conversely, inhibition of CaMKII activity with a peptide (AC3-I) diminishes pathological cardiac remodeling in response to stress (7).…”

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confidence: 99%

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The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

Backs

Neef

et al. 2009

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

389

360

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Acute and chronic injuries to the heart result in perturbation of intracellular calcium signaling, which leads to pathological cardiac hypertrophy and remodeling. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the transduction of calcium signals in the heart, but the specific isoforms of CaMKII that mediate pathological cardiac signaling have not been fully defined. To investigate the potential involvement in heart disease of CaMKII␦, the major CaMKII isoform expressed in the heart, we generated CaMKII␦-null mice. These mice are viable and display no overt abnormalities in cardiac structure or function in the absence of stress. However, pathological cardiac hypertrophy and remodeling are attenuated in response to pressure overload in these animals. Cardiac extracts from CaMKII␦-null mice showed diminished kinase activity toward histone deacetylase 4 (HDAC4), a substrate of stress-responsive protein kinases and suppressor of stress-dependent cardiac remodeling. In contrast, phosphorylation of the closely related HDAC5 was unaffected in hearts of CaMKII␦-null mice, underscoring the specificity of the CaMKII␦ signaling pathway for HDAC4 phosphorylation. We conclude that CaMKII␦ functions as an important transducer of stress stimuli involved in pathological cardiac remodeling in vivo, which is mediated, at least in part, by the phosphorylation of HDAC4. These findings point to CaMKII␦ as a potential therapeutic target for the maintenance of cardiac function in the setting of pressure overload.histone deacetylase 4 (HDAC4) ͉ calcium signaling ͉ excitation contraction coupling (EC coupling) ͉ thoracic aortic constriction (TAC) ͉ CaM Kinase II inhibitory peptide (AC3-I)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

Backs

Neef

et al. 2009

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

389

360

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“…Transgenic mice overexpressing calmodulin were found to develop severe cardiac hypertrophy (19) which was subsequently shown to be associated with an increase in the activity of CaMKII in vivo (20). Pronounced hypertrophy also develops in transgenic mice that overexpress CaMKIV (18) although CaMKIV is not a major CaMK isoform in the heart nor is it required for pressure overload induced hypertrophy (1,21,22). Our laboratory has shown that transgenic mice that overexpress the nuclear targeted cardiac CaMKII␦ B isoform develop hypertrophy, accompanied by cardiomyocyte enlargement and significant increases in hypertrophic gene expression (23).…”

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confidence: 99%

CaMKIIδ Isoforms Differentially Affect Calcium Handling but Similarly Regulate HDAC/MEF2 Transcriptional Responses

Zhang

Kohlhaas

Backs

et al. 2007

Journal of Biological Chemistry

187

168

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The ␦ B and ␦ C splice variants of Ca 2؉ /calmodulin-dependent protein kinase II (CaMKII), which differ by the presence of a nuclear localization sequence, are both expressed in cardiomyocytes. We used transgenic (TG) mice and CaMKII expression in cardiomyocytes to test the hypothesis that the CaMKII␦ C isoform regulates cytosolic Ca 2؉ handling and the ␦ B isoform, which localizes to the nucleus, regulates gene transcription. Phosphorylation of CaMKII sites on the ryanodine receptor (RyR) and on phospholamban (PLB) were increased in CaMKII␦ C TG. This was associated with markedly enhanced sarcoplasmic reticulum (SR) Ca 2؉ spark frequency and decreased SR Ca 2؉ content in cardiomyocytes. None of these parameters were altered in TG mice expressing the nuclear-targeted CaMKII␦ B . In contrast, cardiac expression of either CaMKII␦ B or ␦ C induced transactivation of myocyte enhancer factor 2 (MEF2) gene expression and up-regulated hypertrophic marker genes. Studies using rat ventricular cardiomyocytes confirmed that CaMKII␦ B and ␦ C both regulate MEF2-luciferase gene expression, increase histone deacetylase 4 (HDAC4) association with 14-3-3, and induce HDAC4 translocation from nucleus to cytoplasm, indicating that either isoform can stimulate HDAC4 phosphorylation. Finally, HDAC4 kinase activity was shown to be increased in cardiac homogenates from either CaMKII␦ B or ␦ C TG mice. Thus CaMKII␦ isoforms have similar effects on hypertrophic gene expression but disparate effects on Ca 2؉ handling, suggesting distinct roles for CaMKII␦ isoform activation in the pathogenesis of cardiac hypertrophy versus heart failure.is the predominant isoform of CaMKII in the heart. Splice variants differing in the presence of a nuclear localization sequence (NLS) show distinct subcellular targeting to either cytoplasmic or nuclear compartments (1-3). The CaMKII␦ B isoform contains an 11 amino acid NLS that is absent from ␦ C . Thus CaMKII heteromers comprised predominantly of ␦ B subunits localize to the nucleus while those with predominantly ␦ C localize to the cytoplasm (1-3). We recently demonstrated that both ␦ B and ␦ C CaMKII are activated in response to pressure overload induced by thoracic aortic banding but that expression of these isoforms is differentially regulated (4). The possibility that there are discrete roles for these two isoforms in regulating Ca 2ϩ homeostasis and gene transcription has not yet been explored.CaMKII has long been implicated as a regulator of Ca 2ϩ homeostasis and excitation-contraction (E-C) coupling in ventricular myocytes. This enzyme has been shown to phosphorylate proteins involved in sarcoplasmic reticulum (SR) Ca 2ϩ handling including the cardiac ryanodine receptors (RyR2) and phospholamban (PLB) (4 -10). Phosphorylation of the RyR2 appears to alter its channel open probability (9 -11) while phosphorylation of PLB by CaMKII can regulate SR Ca 2ϩ uptake (10, 12). Altered intracellular Ca 2ϩ handling plays an important role in the pathogenesis of heart failure with changes in Ca 2ϩ cycling pr...

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“…CaMKI and CaMKIV are monomeric enzymes that are activated by phosphorylation through an upstream kinase (CaMK kinase) (Lee and Edelman, 1994;Tokumitsu et al, 1995). These isoforms are expressed at very low levels in the heart (Edman and Schulman, 1994;Colomer et al, 2003). In contrast, CaMKII, the major cardiac isoform, is a multimer of 6 -12 subunits encoded by four separate genes: ␣, ␤, ␥, and ␦ (Braun and Schulman, 1995).…”

Section: ؉ /Calmodulin-dependent Protein Kinasementioning

confidence: 99%

“…This is associated with specific changes in gene expression. However, CaMKIV knockout (KO) mice still are able to develop hypertrophy after TAC (Colomer et al, 2003), presumably because CaMKIV is not one of the major CaMK isoforms present in the heart (Edman and Schulman, 1994;Colomer et al, 2003).…”

Section: The Role Of Camk In Hypertrophic Growthmentioning

confidence: 99%

Cardiomyocyte Calcium and Calcium/Calmodulin-dependent Protein Kinase II: Friends or Foes?

Zhang

Miyamoto²,

Brown³

2004

Recent Progress in Hormone Research

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2ϩ storage and release, transcription factors, and ion channels. The major isoform of CaMKII in the heart is CaMKII␦. Two cardiac splice variants, CaMKII␦ B and ␦ C , differ in whether they contain a nuclear localization sequence. Our laboratory has examined the hypothesis that the nuclear ␦ B and the cytoplasmic ␦ C isoforms respond to different Ca 2ϩ stimuli and have distinct effects on hypertrophic cardiac growth and Ca 2ϩ handling. We have shown that pressure overload-induced hypertrophy differentially affects the nuclear ␦ B and the cytoplasmic ␦ C isoforms of CaMKII. Additionally, using isolated myocytes and transgenic mouse models, we demonstrated that the nuclear CaMKII␦ B isoform plays a key role in cardiac gene expression associated with cardiac hypertrophy. The cytoplasmic CaMKII␦ C isoform phosphorylates substrates involved in Ca 2ϩ handling. Dysregulation of intracellular Ca 2ϩ and resulting changes in excitation-contraction coupling characterize heart failure and can be induced by in vivo overexpression of CaMKII␦ C and phosphorylation of its substrates. The differential location of CaMKII isoforms and their relative activation by physiological vs. pathological stimuli may provide a paradigm for exploring and elucidating how Ca 2ϩ /CaMKII pathways can serve as both friends and foes in the heart.

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Pressure Overload Selectively Up-Regulates Ca²⁺/Calmodulin-Dependent Protein Kinase IIin Vivo

Cited by 88 publications

References 48 publications

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

CaMKIIδ Isoforms Differentially Affect Calcium Handling but Similarly Regulate HDAC/MEF2 Transcriptional Responses

Cardiomyocyte Calcium and Calcium/Calmodulin-dependent Protein Kinase II: Friends or Foes?

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Pressure Overload Selectively Up-Regulates Ca2+/Calmodulin-Dependent Protein Kinase IIin Vivo

Cited by 88 publications

References 48 publications

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

CaMKIIδ Isoforms Differentially Affect Calcium Handling but Similarly Regulate HDAC/MEF2 Transcriptional Responses

Cardiomyocyte Calcium and Calcium/Calmodulin-dependent Protein Kinase II: Friends or Foes?

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Pressure Overload Selectively Up-Regulates Ca²⁺/Calmodulin-Dependent Protein Kinase IIin Vivo