CaMKII as a target for arrhythmia suppression

Mustroph, Julian; Neef, Stefan; Maier, Lars S.

doi:10.1016/j.pharmthera.2016.10.006

Cited by 82 publications

(86 citation statements)

References 115 publications

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“…Strikingly, KN93 abolished arrhythmic contractions and restored the rate of relaxation, time to relaxation, and time to peak to the levels observed in WT KN93‐treated cells. It is noteworthy that KN93 promoted a slight reduction in the cell fractional shortening in the cardiomyocytes of WT and BACHD mice, indicating that CaMKII is an important modulator of cellular electro‐mechanical properties, in accordance with previous findings . We also used the inactive analog KN92 to control for off‐target effects of KN93.…”

Section: Discussionsupporting

confidence: 82%

“…As suggested by Mustroph et al . , strategies aiming to alter CaMKII expression and/or activity could be a new approach to prevent arrhythmias as well as systolic and diastolic ventricular dysfunctions.…”

Section: Discussionmentioning

confidence: 99%

“…The same differences between WT and BACHD were also observed when comparing WT KN92 and BACHD KN92 groups, corroborating the KN93 action. As suggested by Mustroph et al [29], strategies aiming to alter CaMKII expression and/or activity could be a new approach to prevent arrhythmias as well as systolic and diastolic ventricular dysfunctions. Under oxidative conditions, high ROS can enhance the CaMKII activity by direct or indirect pathways [28].…”

Section: Discussionmentioning

confidence: 99%

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Increased oxidative stress and CaMKII activity contribute to electro‐mechanical defects in cardiomyocytes from a murine model of Huntington's disease

et al. 2018

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Huntington's disease (HD) is a neurodegenerative genetic disorder. Although described as a brain pathology, there is evidence suggesting that defects in other systems can contribute to disease progression. In line with this, cardiovascular defects are a major cause of death in HD. To date, relatively little is known about the peripheral abnormalities associated with the disease. Here, we applied a range of assays to evaluate cardiac electro‐mechanical properties in vivo, using a previously characterized mouse model of HD (BACHD), and in vitro, using cardiomyocytes isolated from the same mice. We observed conduction disturbances including QT interval prolongation in BACHD mice, indicative of cardiac dysfunction. Cardiomyocytes from these mice demonstrated cellular electro‐mechanical abnormalities, including a prolonged action potential, arrhythmic contractions, and relaxation disturbances. Cellular arrhythmia was accompanied by an increase in calcium waves and increased Ca2+/calmodulin‐dependent protein kinase II activity, suggesting that disruption of calcium homeostasis plays a key part. We also described structural abnormalities in the mitochondria of BACHD‐derived cardiomyocytes, indicative of oxidative stress. Consistent with this, imbalances in superoxide dismutase and glutathione peroxidase activities were detected. Our data provide an in vivo demonstration of cardiac abnormalities in HD together with new insights into the cellular mechanistic basis, providing a possible explanation for the higher cardiovascular risk in HD.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Increased oxidative stress and CaMKII activity contribute to electro‐mechanical defects in cardiomyocytes from a murine model of Huntington's disease

et al. 2018

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“…In the diseased myocardium, CaMKII plays central roles in processes such as maladaptive remodeling [1, 3, 44, 45, 48, 50, 72, 115, 117], arrhythmogenesis [63], interstitial fibrosis [3, 45] and apoptosis [21, 22, 103, 112]. As such, CaMKII is a promising target for pharmacological inhibition and the development of inhibitory compounds is racing ahead [73].…”

Section: Introductionmentioning

confidence: 99%

Physiological and unappreciated roles of CaMKII in the heart

2018

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In the cardiomyocyte, CaMKII has been identified as a nodal influencer of excitation–contraction and also excitation–transcription coupling. Its activity can be regulated in response to changes in intracellular calcium content as well as after several post-translational modifications. Some of the effects mediated by CaMKII may be considered adaptive, while effects of sustained CaMKII activity may turn into the opposite and are detrimental to cardiac integrity and function. As such, CaMKII has long been noted as a promising target for pharmacological inhibition, but the ubiquitous nature of CaMKII has made it difficult to target CaMKII specifically where it is detrimental. In this review, we provide a brief overview of the physiological and pathophysiological properties of CaMKII signaling, but we focus on the physiological and adaptive functions of CaMKII. Furthermore, special consideration is given to the emerging role of CaMKII as a mediator of inflammatory processes in the heart.

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“…In heart muscle CaMKII is a major actor in Ca 2+ homeostasis, regulating the cardiomyocyte excitability and contractility through the modulation of several channels including the Ltype voltage-gated Ca 2+ channel (15,16). Accordingly, recent studies determined that CaMKII deregulation is an important element in the pathogenesis of arrhythmias and heart failure (17)(18)(19)(20)(21), with CaMKII inhibition suggested as a potential therapy. Despite intense research in several fields for over thirty years, we still do not completely understand how the activation status of CaMKII is regulated.…”

Section: Introductionmentioning

confidence: 99%

The Ras-like GTPase Rem2 is a potent endogenous inhibitor of calcium/calmodulin-dependent kinase II activity

Royer

Herzog

Kenny

et al. 2017

Preprint

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CaMKII is a well-characterized, abundant protein kinase that regulates a diverse set of functions in a tissue specific manner. For example, in heart muscle, CaMKII regulates Ca2+ homeostasis while in neurons CaMKII regulates activity-dependent dendritic remodeling and Long Term Potentiation (LTP), a biological correlate of learning and memory. Previously, we identified the noncanonical GTPase Rem2 as a critical regulator of dendrite branching and synapse formation in the vertebrate nervous system. Here, we report that Rem2 directly interacts with CaMKII and potently inhibits the activity of the intact holoenzyme, a previously undescribed function for the Rem2 protein. To date, only one other endogenous inhibitor of CaMKII has been described: CaMKIIN, which blocks CaMKII activity through binding to the catalytic domain. Our data suggest that Rem2 inhibits CaMKII through a novel mechanism, as inhibition requires the presence of the association domain of CaMKII. Our biochemical finding that Rem2 is a direct, endogenous inhibitor of CaMKII activity, coupled with known functions of Rem2 in neurons, provides a framework which will enable future experiments probing the physiological role of CaMKII inhibition in a cellular context.

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CaMKII as a target for arrhythmia suppression

Cited by 82 publications

References 115 publications

Increased oxidative stress and CaMKII activity contribute to electro‐mechanical defects in cardiomyocytes from a murine model of Huntington's disease

Increased oxidative stress and CaMKII activity contribute to electro‐mechanical defects in cardiomyocytes from a murine model of Huntington's disease

Physiological and unappreciated roles of CaMKII in the heart

The Ras-like GTPase Rem2 is a potent endogenous inhibitor of calcium/calmodulin-dependent kinase II activity

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