Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy

Michelle S C Khoo, Jingdong Li, Madhu V. Singh, Yingbo Yang, Prince Kannankeril, Yuejin Wu, Chad E. Grueter, Xiaoqun Guan, Carmine V. Oddis, Rong Zhang, Lisa Mendes, Gemin Ni, Ernest C. Madu, Jinying Yang, Martha Bass, Rey J. Gomez, Brian E. Wadzinski, Eric N. Olson, Roger J. Colbran, Mark E. Anderson

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

BACKGROUND - Activation of cellular Ca signaling molecules appears to be a fundamental step in the progression of cardiomyopathy and arrhythmias. Myocardial overexpression of the constitutively active Ca-dependent phosphatase calcineurin (CAN) causes severe cardiomyopathy marked by left ventricular (LV) dysfunction, arrhythmias, and increased mortality rate, but CAN antagonist drugs primarily reduce hypertrophy without improving LV function or risk of death. METHODS AND RESULTS - We found that activity and expression of a second Ca-activated signaling molecule, calmodulin kinase II (CaMKII), were increased in hearts from CAN transgenic mice and that CaMKII-inhibitory drugs improved LV function and suppressed arrhythmias. We devised a genetic approach to "clamp" CaMKII activity in CAN mice to control levels by interbreeding CAN transgenic mice with mice expressing a specific CaMKII inhibitor in cardiomyocytes. We developed transgenic control mice by interbreeding CAN transgenic mice with mice expressing an inactive version of the CaMKII-inhibitory peptide. CAN mice with CaMKII inhibition had reduced risk of death and increased LV and ventricular myocyte function and were less susceptible to arrhythmias. CaMKII inhibition did not reduce transgenic overexpression of CAN or expression of endogenous CaMKII protein or significantly reduce most measures of cardiac hypertrophy. CONCLUSIONS - CaMKII is a downstream signal in CAN cardiomyopathy, and increased CaMKII activity contributes to cardiac dysfunction, arrhythmia susceptibility, and longevity during CAN overexpression.

Original languageEnglish (US)
Pages (from-to)1352-1359
Number of pages8
JournalCirculation
Volume114
Issue number13
DOIs
StatePublished - Sep 2006
Externally publishedYes

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinases
Calcineurin
Cardiomyopathies
Cardiac Arrhythmias
Transgenic Mice
Left Ventricular Function
Ventricular Function
Cardiomegaly
Left Ventricular Dysfunction
Cardiac Myocytes
Pharmaceutical Preparations
Muscle Cells
Hypertrophy

Keywords

  • Arrhythmia
  • Calcium
  • Cardiomyopathy
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy. / Khoo, Michelle S C; Li, Jingdong; Singh, Madhu V.; Yang, Yingbo; Kannankeril, Prince; Wu, Yuejin; Grueter, Chad E.; Guan, Xiaoqun; Oddis, Carmine V.; Zhang, Rong; Mendes, Lisa; Ni, Gemin; Madu, Ernest C.; Yang, Jinying; Bass, Martha; Gomez, Rey J.; Wadzinski, Brian E.; Olson, Eric N.; Colbran, Roger J.; Anderson, Mark E.

In: Circulation, Vol. 114, No. 13, 09.2006, p. 1352-1359.

Research output: Contribution to journalArticle

Khoo, MSC, Li, J, Singh, MV, Yang, Y, Kannankeril, P, Wu, Y, Grueter, CE, Guan, X, Oddis, CV, Zhang, R, Mendes, L, Ni, G, Madu, EC, Yang, J, Bass, M, Gomez, RJ, Wadzinski, BE, Olson, EN, Colbran, RJ & Anderson, ME 2006, 'Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy', Circulation, vol. 114, no. 13, pp. 1352-1359. https://doi.org/10.1161/CIRCULATIONAHA.106.644583
Khoo, Michelle S C ; Li, Jingdong ; Singh, Madhu V. ; Yang, Yingbo ; Kannankeril, Prince ; Wu, Yuejin ; Grueter, Chad E. ; Guan, Xiaoqun ; Oddis, Carmine V. ; Zhang, Rong ; Mendes, Lisa ; Ni, Gemin ; Madu, Ernest C. ; Yang, Jinying ; Bass, Martha ; Gomez, Rey J. ; Wadzinski, Brian E. ; Olson, Eric N. ; Colbran, Roger J. ; Anderson, Mark E. / Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy. In: Circulation. 2006 ; Vol. 114, No. 13. pp. 1352-1359.
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abstract = "BACKGROUND - Activation of cellular Ca signaling molecules appears to be a fundamental step in the progression of cardiomyopathy and arrhythmias. Myocardial overexpression of the constitutively active Ca-dependent phosphatase calcineurin (CAN) causes severe cardiomyopathy marked by left ventricular (LV) dysfunction, arrhythmias, and increased mortality rate, but CAN antagonist drugs primarily reduce hypertrophy without improving LV function or risk of death. METHODS AND RESULTS - We found that activity and expression of a second Ca-activated signaling molecule, calmodulin kinase II (CaMKII), were increased in hearts from CAN transgenic mice and that CaMKII-inhibitory drugs improved LV function and suppressed arrhythmias. We devised a genetic approach to {"}clamp{"} CaMKII activity in CAN mice to control levels by interbreeding CAN transgenic mice with mice expressing a specific CaMKII inhibitor in cardiomyocytes. We developed transgenic control mice by interbreeding CAN transgenic mice with mice expressing an inactive version of the CaMKII-inhibitory peptide. CAN mice with CaMKII inhibition had reduced risk of death and increased LV and ventricular myocyte function and were less susceptible to arrhythmias. CaMKII inhibition did not reduce transgenic overexpression of CAN or expression of endogenous CaMKII protein or significantly reduce most measures of cardiac hypertrophy. CONCLUSIONS - CaMKII is a downstream signal in CAN cardiomyopathy, and increased CaMKII activity contributes to cardiac dysfunction, arrhythmia susceptibility, and longevity during CAN overexpression.",
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T1 - Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy

AU - Khoo, Michelle S C

AU - Li, Jingdong

AU - Singh, Madhu V.

AU - Yang, Yingbo

AU - Kannankeril, Prince

AU - Wu, Yuejin

AU - Grueter, Chad E.

AU - Guan, Xiaoqun

AU - Oddis, Carmine V.

AU - Zhang, Rong

AU - Mendes, Lisa

AU - Ni, Gemin

AU - Madu, Ernest C.

AU - Yang, Jinying

AU - Bass, Martha

AU - Gomez, Rey J.

AU - Wadzinski, Brian E.

AU - Olson, Eric N.

AU - Colbran, Roger J.

AU - Anderson, Mark E.

PY - 2006/9

Y1 - 2006/9

N2 - BACKGROUND - Activation of cellular Ca signaling molecules appears to be a fundamental step in the progression of cardiomyopathy and arrhythmias. Myocardial overexpression of the constitutively active Ca-dependent phosphatase calcineurin (CAN) causes severe cardiomyopathy marked by left ventricular (LV) dysfunction, arrhythmias, and increased mortality rate, but CAN antagonist drugs primarily reduce hypertrophy without improving LV function or risk of death. METHODS AND RESULTS - We found that activity and expression of a second Ca-activated signaling molecule, calmodulin kinase II (CaMKII), were increased in hearts from CAN transgenic mice and that CaMKII-inhibitory drugs improved LV function and suppressed arrhythmias. We devised a genetic approach to "clamp" CaMKII activity in CAN mice to control levels by interbreeding CAN transgenic mice with mice expressing a specific CaMKII inhibitor in cardiomyocytes. We developed transgenic control mice by interbreeding CAN transgenic mice with mice expressing an inactive version of the CaMKII-inhibitory peptide. CAN mice with CaMKII inhibition had reduced risk of death and increased LV and ventricular myocyte function and were less susceptible to arrhythmias. CaMKII inhibition did not reduce transgenic overexpression of CAN or expression of endogenous CaMKII protein or significantly reduce most measures of cardiac hypertrophy. CONCLUSIONS - CaMKII is a downstream signal in CAN cardiomyopathy, and increased CaMKII activity contributes to cardiac dysfunction, arrhythmia susceptibility, and longevity during CAN overexpression.

AB - BACKGROUND - Activation of cellular Ca signaling molecules appears to be a fundamental step in the progression of cardiomyopathy and arrhythmias. Myocardial overexpression of the constitutively active Ca-dependent phosphatase calcineurin (CAN) causes severe cardiomyopathy marked by left ventricular (LV) dysfunction, arrhythmias, and increased mortality rate, but CAN antagonist drugs primarily reduce hypertrophy without improving LV function or risk of death. METHODS AND RESULTS - We found that activity and expression of a second Ca-activated signaling molecule, calmodulin kinase II (CaMKII), were increased in hearts from CAN transgenic mice and that CaMKII-inhibitory drugs improved LV function and suppressed arrhythmias. We devised a genetic approach to "clamp" CaMKII activity in CAN mice to control levels by interbreeding CAN transgenic mice with mice expressing a specific CaMKII inhibitor in cardiomyocytes. We developed transgenic control mice by interbreeding CAN transgenic mice with mice expressing an inactive version of the CaMKII-inhibitory peptide. CAN mice with CaMKII inhibition had reduced risk of death and increased LV and ventricular myocyte function and were less susceptible to arrhythmias. CaMKII inhibition did not reduce transgenic overexpression of CAN or expression of endogenous CaMKII protein or significantly reduce most measures of cardiac hypertrophy. CONCLUSIONS - CaMKII is a downstream signal in CAN cardiomyopathy, and increased CaMKII activity contributes to cardiac dysfunction, arrhythmia susceptibility, and longevity during CAN overexpression.

KW - Arrhythmia

KW - Calcium

KW - Cardiomyopathy

KW - Signal transduction

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