Cardiac CaM kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy

Michael M. Kreusser, Lorenz H. Lehmann, Stanislav Keranov, Marc Oscar Hoting, Ulrike Oehl, Michael Kohlhaas, Jan Christian Reil, Kay Neumann, Michael D. Schneider, Joseph A Hill, Dobromir Dobrev, Christoph Maack, Lars S. Maier, Hermann Josef Gröne, Hugo A. Katus, Eric N Olson, Johannes Backs

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Background-Ca<sup>2+</sup>-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. Methods and Results-We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca<sup>2+</sup> handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. Conclusions-We established a mouse model in which CaMKII's activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.

Original languageEnglish (US)
Pages (from-to)1262-1273
Number of pages12
JournalCirculation
Volume130
Issue number15
DOIs
StatePublished - 2014

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcineurin
Hypertrophy
Knockout Mice
Genes
Cardiomegaly
Phosphorylation
Ryanodine Receptor Calcium Release Channel
Histone Deacetylases
Cardiac Myocytes
Adrenergic Agents
Protein Isoforms
Fibrosis
Heart Failure
Pressure

Keywords

  • Calcineurin
  • CaMKII
  • Cardiac hypertrophy
  • Heart failure
  • Signal transduction

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Cardiac CaM kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy. / Kreusser, Michael M.; Lehmann, Lorenz H.; Keranov, Stanislav; Hoting, Marc Oscar; Oehl, Ulrike; Kohlhaas, Michael; Reil, Jan Christian; Neumann, Kay; Schneider, Michael D.; Hill, Joseph A; Dobrev, Dobromir; Maack, Christoph; Maier, Lars S.; Gröne, Hermann Josef; Katus, Hugo A.; Olson, Eric N; Backs, Johannes.

In: Circulation, Vol. 130, No. 15, 2014, p. 1262-1273.

Research output: Contribution to journalArticle

Kreusser, MM, Lehmann, LH, Keranov, S, Hoting, MO, Oehl, U, Kohlhaas, M, Reil, JC, Neumann, K, Schneider, MD, Hill, JA, Dobrev, D, Maack, C, Maier, LS, Gröne, HJ, Katus, HA, Olson, EN & Backs, J 2014, 'Cardiac CaM kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy', Circulation, vol. 130, no. 15, pp. 1262-1273. https://doi.org/10.1161/CIRCULATIONAHA.114.006185
Kreusser, Michael M. ; Lehmann, Lorenz H. ; Keranov, Stanislav ; Hoting, Marc Oscar ; Oehl, Ulrike ; Kohlhaas, Michael ; Reil, Jan Christian ; Neumann, Kay ; Schneider, Michael D. ; Hill, Joseph A ; Dobrev, Dobromir ; Maack, Christoph ; Maier, Lars S. ; Gröne, Hermann Josef ; Katus, Hugo A. ; Olson, Eric N ; Backs, Johannes. / Cardiac CaM kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy. In: Circulation. 2014 ; Vol. 130, No. 15. pp. 1262-1273.
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abstract = "Background-Ca2+-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. Methods and Results-We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca2+ handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. Conclusions-We established a mouse model in which CaMKII's activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.",
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T1 - Cardiac CaM kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy

AU - Kreusser, Michael M.

AU - Lehmann, Lorenz H.

AU - Keranov, Stanislav

AU - Hoting, Marc Oscar

AU - Oehl, Ulrike

AU - Kohlhaas, Michael

AU - Reil, Jan Christian

AU - Neumann, Kay

AU - Schneider, Michael D.

AU - Hill, Joseph A

AU - Dobrev, Dobromir

AU - Maack, Christoph

AU - Maier, Lars S.

AU - Gröne, Hermann Josef

AU - Katus, Hugo A.

AU - Olson, Eric N

AU - Backs, Johannes

PY - 2014

Y1 - 2014

N2 - Background-Ca2+-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. Methods and Results-We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca2+ handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. Conclusions-We established a mouse model in which CaMKII's activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.

AB - Background-Ca2+-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. Methods and Results-We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca2+ handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. Conclusions-We established a mouse model in which CaMKII's activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.

KW - Calcineurin

KW - CaMKII

KW - Cardiac hypertrophy

KW - Heart failure

KW - Signal transduction

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