Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels

Wagner, Stefan; Dybkova, Nataliya; Rasenack, Eva C.L.; Jacobshagen, Claudius; Fabritz, Larissa; Kirchhof, Paulus; Maier, Sebastian; Zhang, Tong; Hasenfuß, Gerd; Brown, Joan Heller; Bers, Donald M.; Maier, Lars S.

doi:10.1172/jci26620

Cited by 483 publications

(616 citation statements)

References 43 publications

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“…In particular, CAMKII‐dependent phosphorylation of Nav1.5 alters I Na gating by reducing current availability at higher pacing rates 27. Moreover, transgenic overexpression of CAMKIIδ promotes QRS prolongation and increases predisposition for VT/VF 27. Indeed, phosphoactive CAMKII levels were markedly upregulated in our porcine MI model in agreement with previous results in human and canine models of ischemic heart failure 32.…”

Section: Discussionsupporting

confidence: 89%

“…Therefore, we surmised that the differences in the rate dependence of myocardial conduction and excitability are likely related to differences in Na channel activity rather than expression. In recent years, studies have focused on the intricate regulation of Nav1.5 activity by CaMKII,24, 25, 26, 27 a key calcium‐dependent kinase that is activated in MI. In particular, CAMKII activation was shown to modulate Na channel recovery from inactivation 27.…”

Section: Resultsmentioning

confidence: 99%

“…In recent years, studies have focused on the intricate regulation of Nav1.5 activity by CaMKII,24, 25, 26, 27 a key calcium‐dependent kinase that is activated in MI. In particular, CAMKII activation was shown to modulate Na channel recovery from inactivation 27. We therefore measured the expression levels of phosphoactive CAMKII (phosphorylated at Thr‐287, pCaMKII) levels in control, MI, and MI+SERCA2a hearts.…”

Section: Resultsmentioning

confidence: 99%

“…CAMKII, a calcium‐sensitive kinase that is activated post‐MI, regulates Na channel activity in a rate‐dependent manner 24, 25, 27. In particular, CAMKII‐dependent phosphorylation of Nav1.5 alters I Na gating by reducing current availability at higher pacing rates 27.…”

Section: Discussionmentioning

confidence: 99%

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Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Motloch

Cacheux

Ishikawa

et al. 2018

JAHA

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Background SERCA2a gene transfer (GT) improves mechano‐electrical function in animal models of nonischemic heart failure Whether SERCA2a GT reverses pre‐established remodeling at an advanced stage of ischemic heart failure is unclear. We sought to uncover the electrophysiological effects of adeno‐associated virus serotype 1.SERCA2a GT following myocardial infarction (MI).Methods and ResultsPigs developed mechanical dysfunction 1 month after anterior MI, at which point they received intracoronary adeno‐associated virus serotype 1.SERCA2a (MI+SERCA2a) or saline (MI) and were maintained for 2 months. Age‐matched naive pigs served as controls (Control). In vivo ECG‐and‐hemodynamic properties were assessed before and after dobutamine stress. The electrophysiological substrate was measured using optical action potential (AP) mapping in controls, MI, and MI+SERCA2a preparations. In vivo ECG measurements revealed comparable QT durations between groups. In contrast, prolonged QRS duration and increased frequency of R′ waves were present in MI but not MI+SERCA2a pigs relative to controls. SERCA2a GT reduced in in vivo arrhythmias in response to dobutamine. Ex vivo preparations from MI but not MI+SERCA2a or control pigs were prone to pacing‐induced ventricular tachycardia and fibrillation. Underlying these arrhythmias was pronounced conduction velocity slowing in MI versus MI+SERCA2a at elevated rates leading to ventricular tachycardia and fibrillation. Reduced susceptibility to ventricular tachycardia and fibrillation in MI+SERCA2a pigs was not related to hemodynamic function, contractile reserve, fibrosis, or the expression of Cx43 and Nav1.5. Rather, SERCA2a GT decreased phosphoactive CAMKII‐delta levels by >50%, leading to improved excitability at fast rates.Conclusions SERCA2a GT increases conduction velocity reserve, likely by preventing CAMKII overactivation. Our findings suggest a primary effect of SERCA2a GT on myocardial excitability, independent of altered mechanical function.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Motloch

Cacheux

Ishikawa

et al. 2018

JAHA

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“…A growing body of evidence has demonstrated that CaMKII can also be activated by ROS 21, 22, 23, 24. Once activated, CaMKII can phosphorylate a wide range of key Ca 2+ and Na + regulatory proteins such as LCCs,25, 26, 27, 28 RyRs,29, 30, 31, 32, 33, 34, 35 phosphalamban,29, 34, 36 and Na + channels 37, 38. Importantly, Xie et al39 showed that H 2 O 2 perfusion–induced oxidative CaMKII activation leads to afterdepolarizations in isolated rabbit cardiomyocytes, likely by phosphorylation of Na + channels and LCCs.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial‐Mediated Oxidative Ca ²⁺ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

Yang

Erñst

Song

et al. 2018

JAHA

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BackgroundOxidative stress–mediated Ca2+/calmodulin‐dependent protein kinase II (CaMKII) phosphorylation of cardiac ion channels has emerged as a critical contributor to arrhythmogenesis in cardiac pathology. However, the link between mitochondrial‐derived reactive oxygen species (mdROS) and increased CaMKII activity in the context of cardiac arrhythmias has not been fully elucidated and is difficult to establish experimentally.Methods and ResultsWe hypothesize that pathological mdROS can cause erratic action potentials through the oxidation‐dependent CaMKII activation pathway. We further propose that CaMKII‐dependent phosphorylation of sarcolemmal slow Na+ channels alone is sufficient to elicit early afterdepolarizations. To test the hypotheses, we expanded our well‐established guinea pig cardiomyocyte excitation‐contraction coupling, mitochondrial energetics, and ROS‐induced‐ROS‐release model by incorporating oxidative CaMKII activation and CaMKII‐dependent Na+ channel phosphorylation in silico. Simulations show that mdROS mediated‐CaMKII activation elicits early afterdepolarizations by augmenting the late Na+ currents, which can be suppressed by blocking L‐type Ca2+ channels or Na+/Ca2+ exchangers. Interestingly, we found that oxidative CaMKII activation–induced early afterdepolarizations are sustained even after mdROS has returned to its physiological levels. Moreover, mitochondrial‐targeting antioxidant treatment can suppress the early afterdepolarizations, but only if given in an appropriate time window. Incorporating concurrent mdROS‐induced ryanodine receptors activation further exacerbates the proarrhythmogenic effect of oxidative CaMKII activation.ConclusionsWe conclude that oxidative CaMKII activation–dependent Na channel phosphorylation is a critical pathway in mitochondria‐mediated cardiac arrhythmogenesis.

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The late sodium current in heart failure: pathophysiology and clinical relevance

Horváth

Bers

2014

ESC Heart Failure

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Large and growing body of data suggest that an increased late sodium current (I Na,late ) can have a significant pathophysiological role in heart failure and other heart diseases. The first goal of this article is to describe how I Na,late functions under physiological circumstances. The second goal is to show the wide range of cellular mechanisms that can increase I Na,late in cardiac disease, and also to describe how the up-regulated I Na,late contributes to the pathophysiology of heart failure. The final section of the article discusses the possible use of I Na,late -modifying drugs in heart failure, on the basis of experimental and preclinical data.

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Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels

Cited by 483 publications

References 43 publications

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Mitochondrial‐Mediated Oxidative Ca ²⁺ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

The late sodium current in heart failure: pathophysiology and clinical relevance

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Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels

Cited by 483 publications

References 43 publications

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Mitochondrial‐Mediated Oxidative Ca 2+ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

The late sodium current in heart failure: pathophysiology and clinical relevance

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Mitochondrial‐Mediated Oxidative Ca ²⁺ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study