Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis

Yan, Jiajie; Zhao, Weiwei; Thomson, Justin K.; Gao, Xianlong; DeMarco, Dominic M.; Carrillo, Elena F. Pérez; Chen, Biyi; Wu, Xiaomin; Ginsburg, Kenneth S.; Bakhos, Mamdouh; Bers, Donald M.; Anderson, Mark E.; Song, Long‐Sheng; Fill, Michael; Ai, Xun

doi:10.1161/circresaha.117.312536

Cited by 68 publications

(47 citation statements)

References 52 publications

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“…Cooper et al (2013) also demonstrated that, in the presence of β-adrenergic agonist isoproterenol, RyR2 phosphorylation at CaMKII site Serine-2814 was significantly increased in ventricular myocytes from old rabbit hearts (four to six years old) in comparison to young (five to nine months old) [9]. A significantly increased activity of stress response kinase JNK2 was reported to activate CaMKII and, thus, upregulate RyR2-mediated diastolic SR Ca 2+ leak in aged mouse atria (24–32 months old) [39]. Guo et al (2014) observed increased RyR2 phosphorylation at CaMKII-specific site S2814 in aged mouse atrial myocytes, which increased aberrant intracellular waves and facilitated AF initiation [40].…”

Section: Intracellular Ca2+ Homeostasis In the Aged Heartmentioning

confidence: 99%

Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart

Hamilton

Terentyev

2019

IJMS

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Aging of the heart is associated with a blunted response to sympathetic stimulation, reduced contractility, and increased propensity for arrhythmias, with the risk of sudden cardiac death significantly increased in the elderly population. The altered cardiac structural and functional phenotype, as well as age-associated prevalent comorbidities including hypertension and atherosclerosis, predispose the heart to atrial fibrillation, heart failure, and ventricular tachyarrhythmias. At the cellular level, perturbations in mitochondrial function, excitation-contraction coupling, and calcium homeostasis contribute to this electrical and contractile dysfunction. Major determinants of cardiac contractility are the intracellular release of Ca2+ from the sarcoplasmic reticulum by the ryanodine receptors (RyR2), and the following sequestration of Ca2+ by the sarco/endoplasmic Ca2+-ATPase (SERCa2a). Activity of RyR2 and SERCa2a in myocytes is not only dependent on expression levels and interacting accessory proteins, but on fine-tuned regulation via post-translational modifications. In this paper, we review how aberrant changes in intracellular Ca2+ cycling via these proteins contributes to arrhythmogenesis in the aged heart.

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Section: Intracellular Ca2+ Homeostasis In the Aged Heartmentioning

confidence: 99%

Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart

Hamilton

Terentyev

2019

IJMS

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“…Concerning AF, the cardiomyocyte sleeves overlapping the pulmonary veins along with Ca 2+ handling disorders are the sources of the ectopic electrical activity, while re-entry circuits are promoted by the atrial tissue heterogeneity and disorders in the intercellular electrical coupling mediated by connexin (Cx) channels [3,5,8,9,[30][31][32][33][34]. The association of AF with the atrial Cx37 and Cx40 gene polymorphisms [35], as well as somatic mutations in GJA5 (encoding Cx40), have been identified in AF [36,37].…”

Section: A Short Overview On Afmentioning

confidence: 99%

Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism

Tribulová

Kurahara

Hlivák

et al. 2020

IJMS

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A perennial task is to prevent the occurrence and/or recurrence of most frequent or life-threatening cardiac arrhythmias such as atrial fibrillation (AF) and ventricular fibrillation (VF). VF may be lethal in cases without an implantable cardioverter defibrillator or with failure of this device. Incidences of AF, even the asymptomatic ones, jeopardize the patient’s life due to its complication, notably the high risk of embolic stroke. Therefore, there has been a growing interest in subclinical AF screening and searching for novel electrophysiological and molecular markers. Considering the worldwide increase in cases of thyroid dysfunction and diseases, including thyroid carcinoma, we aimed to explore the implication of thyroid hormones in pro-arrhythmic signaling in the pathophysiological setting. The present review provides updated information about the impact of altered thyroid status on both the occurrence and recurrence of cardiac arrhythmias, predominantly AF. Moreover, it emphasizes the importance of both thyroid status monitoring and AF screening in the general population, as well as in patients with thyroid dysfunction and malignancies. Real-world data on early AF identification in relation to thyroid function are scarce. Even though symptomatic AF is rare in patients with thyroid malignancies, who are under thyroid suppressive therapy, clinicians should be aware of potential interaction with asymptomatic AF. It may prevent adverse consequences and improve the quality of life. This issue may be challenging for an updated registry of AF in clinical practice. Thyroid hormones should be considered a biomarker for cardiac arrhythmias screening and their tailored management because of their multifaceted cellular actions.

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“…Though this discussion of potential pharmacological targets is certainly not exhaustive, a final therapeutic intervention involves c-Jun N-terminal kinase, or JNK. This kinase, responsible for the activation of CaMKII, is a factor in the development of atrial arrhythmias [ 143 ]. Left unchecked, this pathway results in the disturbance of diastolic calcium handling, as mentioned earlier in the review [ 143 , 144 ].…”

Section: Dietary and Pharmacological Interventionsmentioning

confidence: 99%

“…This kinase, responsible for the activation of CaMKII, is a factor in the development of atrial arrhythmias [ 143 ]. Left unchecked, this pathway results in the disturbance of diastolic calcium handling, as mentioned earlier in the review [ 143 , 144 ]. Targeted inhibition of JNK could be yet another mechanism for combatting the oxidative stress and pro-arrhythmogenic effects of a chronic HFD.…”

Section: Dietary and Pharmacological Interventionsmentioning

confidence: 99%

Mechanisms of Chronic Metabolic Stress in Arrhythmias

et al. 2020

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Cardiac arrhythmias are responsible for many cardiovascular disease-related deaths worldwide. While arrhythmia pathogenesis is complex, there is increasing evidence for metabolic causes. Obesity, diabetes, and chronically consuming high-fat foods significantly increase the likelihood of developing arrhythmias. Although these correlations are well established, mechanistic explanations connecting a high-fat diet (HFD) to arrhythmogenesis are incomplete, although oxidative stress appears to be critical. This review investigates the metabolic changes that occur in obesity and after HFD. Potential therapies to prevent or treat arrhythmias are discussed, including antioxidants.

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Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis

Abstract: We have identified JNK2-driven CaMKII activation as a novel mode of kinase crosstalk and a causal factor in atrial arrhythmic remodeling, making JNK2 a compelling new therapeutic target for AF prevention and treatment.

Cited by 68 publications

References 52 publications

Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart

Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart

Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism

Mechanisms of Chronic Metabolic Stress in Arrhythmias

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