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 J.; Wu, Yuejin; Grueter, Chad E.; Guan, Xiaoqun; Oddis, Carmine V.; Zhang, Rong; Mendes, Lisa A.; Ni, Gemin; Madu, Ernest; Yang, Jinying; Bass, Martha A.; Gomez, Rey J.; Wadzinski, Brian E.; Olson, Eric N.; Colbran, Roger J.; Anderson, Mark E.

doi:10.1161/circulationaha.106.644583

Cited by 103 publications

(88 citation statements)

References 38 publications

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“…Our data in Ryr2 S2814A knockin mice suggest that phosphorylation of S2814 on RyR2 is the major, but presumably not the only, downstream target of CaMKII during AF evolution. CaMKII is a known proarrhythmic signal and a promising therapeutic target for prevention of ventricular arrhythmias and sudden death (57). Our new findings expand the impact and scope of these earlier studies by showing that CaMKII inhibition could be a new approach to treating AF.…”

Section: Figuresupporting

confidence: 64%

Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice

Chelu¹,

Sarma²,

Sood³

et al. 2009

J. Clin. Invest.

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218

245

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Atrial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca 2+ handling. Diastolic Ca 2+ release from the sarcoplasmic reticulum via "leaky" ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2 R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice.

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Section: Figuresupporting

confidence: 64%

Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice

Chelu¹,

Sarma²,

Sood³

et al. 2009

J. Clin. Invest.

Self Cite

218

245

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show abstract

“…[16][17][18], transcription factors, and cell death pathways (19)(20)(21)(22). Finally, CaMKII inhibition has shown exciting promise for the treatment of excitable cell disease (5,(23)(24)(25)(26). Collectively, these data strongly support the notion that local CaMKII/effector signaling nodes represent key cellular rheostats to translate local alterations in the cellular environment to global changes in membrane excitability and organism function.…”

Section: Introductionmentioning

confidence: 61%

A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice

Hund¹,

Koval²,

Li³

et al. 2010

J. Clin. Invest.

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231

289

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Ion channel function is fundamental to the existence of life. In metazoans, the coordinate activities of voltagegated Na + channels underlie cellular excitability and control neuronal communication, cardiac excitationcontraction coupling, and skeletal muscle function. However, despite decades of research and linkage of Na + channel dysfunction with arrhythmia, epilepsy, and myotonia, little progress has been made toward understanding the fundamental processes that regulate this family of proteins. Here, we have identified β IV -spectrin as a multifunctional regulatory platform for Na + channels in mice. We found that β IV -spectrin targeted critical structural and regulatory proteins to excitable membranes in the heart and brain. Animal models harboring mutant β IV -spectrin alleles displayed aberrant cellular excitability and whole animal physiology. Moreover, we identified a regulatory mechanism for Na + channels, via direct phosphorylation by β IV -spectrin-targeted calcium/calmodulin-dependent kinase II (CaMKII). Collectively, our data define an unexpected but indispensable molecular platform that determines membrane excitability in the mouse heart and brain.

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“…CaMKII has emerged as a core signaling molecule in contracting and pacemaking myocardial cells, because CaMKII catalyzes the phosphorylation of most major Ca 2+ homeostatic proteins (14) that orchestrate the mechanical force-frequency relationship (28) and enable fightor-flight increases in HR (4). Under disease conditions, excessive autonomous CaMKII activity can result from oxidation (29), and a growing body of evidence supports the concept that unconstrained and excessive CaMKII activity contributes to heart failure (12,30), arrhythmias (12,(30)(31)(32)(33)(34), and sudden death (35,36). CaMKII stimulation of apoptosis is an important component of the cardiomyopathic effects of excessive CaMKII activity (11,37,38).…”

Section: Discussionmentioning

confidence: 99%

Oxidized CaMKII causes cardiac sinus node dysfunction in mice

et al. 2011

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Sinus node dysfunction (SND) is a major public health problem that is associated with sudden cardiac death and requires surgical implantation of artificial pacemakers. However, little is known about the molecular and cellular mechanisms that cause SND. Most SND occurs in the setting of heart failure and hypertension, conditions that are marked by elevated circulating angiotensin II (Ang II) and increased oxidant stress. Here, we show that oxidized calmodulin kinase II (ox-CaMKII) is a biomarker for SND in patients and dogs and a disease determinant in mice. In wild-type mice, Ang II infusion caused sinoatrial nodal (SAN) cell oxidation by activating NADPH oxidase, leading to increased ox-CaMKII, SAN cell apoptosis, and SND. p47 --mice lacking functional NADPH oxidase and mice with myocardial or SAN-targeted CaMKII inhibition were highly resistant to SAN apoptosis and SND, suggesting that ox-CaMKII-triggered SAN cell death contributed to SND. We developed a computational model of the sinoatrial node that showed that a loss of SAN cells below a critical threshold caused SND by preventing normal impulse formation and propagation. These data provide novel molecular and mechanistic information to understand SND and suggest that targeted CaMKII inhibition may be useful for preventing SND in high-risk patients. IntroductionEach normal heart beat is initiated as an electrical impulse from a small number of highly specialized sinoatrial node (SAN) pacemaker cells that reside in the lateral right atrium. There is now general agreement that physiological SAN function requires a pacemaker current (I f ) (1) and spontaneous release of sarcoplasmic reticulum (SR) intracellular Ca 2+ that triggers depolarizing current through the Na + /Ca 2+ exchanger (I NCX ) (2, 3). The multifunctional Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is essential for increasing SR Ca 2+ release in SAN cells in response to stress to cause physiological "fight-or-flight" heart rate (HR) increases (4). Although the physiological basis for SAN behavior is increasingly understood, very little is known about SAN disease. Severe SAN dysfunction (SND) is marked by irregular prolonged pauses between heart beats, pathologically slow HRs at rest, and inadequate activity-related increases in HR. At present, surgical implantation of permanent pacemakers is required for treatment of SND and costs $2 billion annually in the United States (5). SND commonly occurs in the setting of heart failure and hypertension (6-8), conditions characterized by excessive activation of renin-Ang II signaling (9) and elevated levels of ROS (10). Ang II increases ROS in ventricular myocardium by stimulating NADPH oxidase to cause activation of CaMKII (ox-CaMKII) by oxidation of Met281/282 in the CaMKII regulatory domain (11).

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Death, Cardiac Dysfunction, and Arrhythmias Are Increased by Calmodulin Kinase II in Calcineurin Cardiomyopathy

Cited by 103 publications

References 38 publications

Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice

Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice

A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice

Oxidized CaMKII causes cardiac sinus node dysfunction in mice

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