SR-targeted CaMKII inhibition improves SR Ca2+ handling, but accelerates cardiac remodeling in mice overexpressing CaMKIIδC

Sabine Huke, Jaime DeSantiago, Marcia A. Kaetzel, Shikha Mishra, Joan H. Brown, John R. Dedman, Donald M Bers

Research output: Contribution to journalArticle

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Abstract

Cardiac myocyte overexpression of CaMKIIδC leads to cardiac hypertrophy and heart failure (HF) possibly caused by altered myocyte Ca2+ handling. A central defect might be the marked CaMKII-induced increase in diastolic sarcoplasmic reticulum (SR) Ca2+ leak which decreases SR Ca2+ load and Ca2+ transient amplitude. We hypothesized that inhibition of CaMKII near the SR membrane would decrease the leak, improve Ca2+ handling and prevent the development of contractile dysfunction and HF. To test this hypothesis we crossbred CaMKIIδC overexpressing mice (CaMK) with mice expressing the CaMKII-inhibitor AIP targeted to the SR via a modified phospholamban (PLB)-transmembrane-domain (SR-AIP). There was a selective decrease in the amount of activated CaMKII in the microsomal (SR/membrane) fraction prepared from these double-transgenic mice (CaMK/SR-AIP) mice. In ventricular cardiomyocytes from CaMK/SR-AIP mice, SR Ca2+ leak, assessed both as diastolic Ca2+ shift into SR upon tetracaine in intact myocytes or integrated Ca2+ spark release in permeabilized myocytes, was significantly reduced. The reduced leak was accompanied by enhanced SR Ca2+ load and twitch amplitude in double-transgenic mice (vs. CaMK), without changes in SERCA expression or NCX function. However, despite the improved myocyte Ca2+ handling, cardiac hypertrophy and remodeling was accelerated in CaMK/SR-AIP and cardiac function worsened. We conclude that while inhibition of SR localized CaMKII in CaMK mice improves Ca2+ handling, it does not necessarily rescue the HF phenotype. This implies that a non-SR CaMKIIδC exerts SR-independent effects that contribute to hypertrophy and HF, and this CaMKII pathway may be exacerbated by the global enhancement of Ca transients.

Original languageEnglish (US)
Pages (from-to)230-238
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume50
Issue number1
DOIs
StatePublished - Jan 2011

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Sarcoplasmic Reticulum
Heart Failure
Muscle Cells
Cardiomegaly
Cardiac Myocytes
Transgenic Mice
Tetracaine
Reticulum
Membranes
Hypertrophy

Keywords

  • Ca2+ sparks
  • Ca2+/Calmodulin-dependent kinase
  • Diastolic Ca2+ leak
  • Excitation-contraction coupling
  • Heart failure
  • Transgenic mice

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

SR-targeted CaMKII inhibition improves SR Ca2+ handling, but accelerates cardiac remodeling in mice overexpressing CaMKIIδC. / Huke, Sabine; DeSantiago, Jaime; Kaetzel, Marcia A.; Mishra, Shikha; Brown, Joan H.; Dedman, John R.; Bers, Donald M.

In: Journal of Molecular and Cellular Cardiology, Vol. 50, No. 1, 01.2011, p. 230-238.

Research output: Contribution to journalArticle

Huke, Sabine ; DeSantiago, Jaime ; Kaetzel, Marcia A. ; Mishra, Shikha ; Brown, Joan H. ; Dedman, John R. ; Bers, Donald M. / SR-targeted CaMKII inhibition improves SR Ca2+ handling, but accelerates cardiac remodeling in mice overexpressing CaMKIIδC. In: Journal of Molecular and Cellular Cardiology. 2011 ; Vol. 50, No. 1. pp. 230-238.
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AU - Kaetzel, Marcia A.

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AU - Brown, Joan H.

AU - Dedman, John R.

AU - Bers, Donald M

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AB - Cardiac myocyte overexpression of CaMKIIδC leads to cardiac hypertrophy and heart failure (HF) possibly caused by altered myocyte Ca2+ handling. A central defect might be the marked CaMKII-induced increase in diastolic sarcoplasmic reticulum (SR) Ca2+ leak which decreases SR Ca2+ load and Ca2+ transient amplitude. We hypothesized that inhibition of CaMKII near the SR membrane would decrease the leak, improve Ca2+ handling and prevent the development of contractile dysfunction and HF. To test this hypothesis we crossbred CaMKIIδC overexpressing mice (CaMK) with mice expressing the CaMKII-inhibitor AIP targeted to the SR via a modified phospholamban (PLB)-transmembrane-domain (SR-AIP). There was a selective decrease in the amount of activated CaMKII in the microsomal (SR/membrane) fraction prepared from these double-transgenic mice (CaMK/SR-AIP) mice. In ventricular cardiomyocytes from CaMK/SR-AIP mice, SR Ca2+ leak, assessed both as diastolic Ca2+ shift into SR upon tetracaine in intact myocytes or integrated Ca2+ spark release in permeabilized myocytes, was significantly reduced. The reduced leak was accompanied by enhanced SR Ca2+ load and twitch amplitude in double-transgenic mice (vs. CaMK), without changes in SERCA expression or NCX function. However, despite the improved myocyte Ca2+ handling, cardiac hypertrophy and remodeling was accelerated in CaMK/SR-AIP and cardiac function worsened. We conclude that while inhibition of SR localized CaMKII in CaMK mice improves Ca2+ handling, it does not necessarily rescue the HF phenotype. This implies that a non-SR CaMKIIδC exerts SR-independent effects that contribute to hypertrophy and HF, and this CaMKII pathway may be exacerbated by the global enhancement of Ca transients.

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