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

Michelle S. C KHOO; JINGDONG LI; 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; Madhu V SINGH; YINGBO YANG; Prince KANNANKERIL; YUEJIN WU; Chad E GRUETER; XIAOQUN GUAN; Carmine V ODDIS; RONG ZHANG

doi:10.1161/CIRCULATIONAHA.106.644583

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

Journal article

Open access

Peer reviewed

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

Michelle S. C KHOO, JINGDONG LI, Lisa MENDES, GEMIN NI, Ernest C MADU, JINYING YANG, Martha BASS, Rey J GOMEZ, Brian E WADZINSKI, Eric N OLSON, …

Circulation (New York, N.Y.), Vol.114(13), pp.1352-1359

2006

DOI: 10.1161/CIRCULATIONAHA.106.644583

PMID: 16982937

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Abstract

Background: Activation of cellular Ca2+ signaling molecules appears to be a fundamental step in the progression of cardiomyopathy and arrhythmias. Myocardial overexpression of the constitutively active Ca2+-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 Ca2+-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.

Heart

Fundamental and applied biological sciences. Psychology

Cardiology. Vascular system

Platelet

Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous

Biological and medical sciences

Blood coagulation. Blood cells

Molecular and cellular biology

Medical sciences

Coronary heart disease

Blood and lymphatic vessels

Details

Title: Subtitle: Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy
Creators: Michelle S. C KHOO - Department of Medicine, Vanderbilt University, Nashville, Tenn, United States
JINGDONG LI - Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Lisa MENDES - Department of Medicine, Vanderbilt University, Nashville, Tenn, United States
GEMIN NI - Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States
Ernest C MADU - Division of Cardiovascular Medicine, Heart Institute of the Caribbean, Kingston, Jamaica
JINYING YANG - Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States
Martha BASS - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tenn, United States
Rey J GOMEZ - Department of Pharmacology, Vanderbilt University, Nashville, Tenn, United States
Brian E WADZINSKI - Department of Pharmacology, Vanderbilt University, Nashville, Tenn, United States
Eric N OLSON - Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Tex, United States
Roger J COLBRAN - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tenn, United States
Mark E ANDERSON - Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States
Madhu V SINGH - Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States
YINGBO YANG - Department of Medicine, Vanderbilt University, Nashville, Tenn, United States
Prince KANNANKERIL - Department of Pediatrics, Vanderbilt University, Nashville, Tenn, United States
YUEJIN WU - Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States
Chad E GRUETER - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tenn, United States
XIAOQUN GUAN - Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States
Carmine V ODDIS - Department of Medicine, Vanderbilt University, Nashville, Tenn, United States
RONG ZHANG - Department of Medicine, Vanderbilt University, Nashville, Tenn, United States
Resource Type: Journal article
Publication Details: Circulation (New York, N.Y.), Vol.114(13), pp.1352-1359
DOI: 10.1161/CIRCULATIONAHA.106.644583
PMID: 16982937
NLM abbreviation: Circulation
ISSN: 0009-7322
eISSN: 1524-4539
Publisher: Lippincott Williams & Wilkins
Language: English
Date published: 2006
Academic Unit: Cardiovascular Medicine; Craniofacial Anomalies Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984094575302771

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