CLOCK-BMAL1 regulate the cardiac L-type calcium channel subunit CACNA1C through PI3K-Akt signaling pathway

Chen, Yanhong; Zhu, Didi; Yuan, Jing; Han, Zhonglin; Wang, Yao; Zhang, Qian; Hou, Xiaofeng; Wu, Tingting; Zou, Jiangang

doi:10.1139/cjpp-2015-0398

Cited by 31 publications

(47 citation statements)

References 41 publications

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“…Many drug metabolizing enzymes, transporters, and targets were found cycling in the cardiovascular system. Circadian clock-dependent variation in cardiac ion channels has been shown in animal models (32)(33)(34) and is proposed to underlie time-dependent arrhythmias and sudden cardiac death in humans (35,36). We found that several L-type Ca 2+ channel subunits -critical for cardiac polarization and targets of commonly prescribed antihypertensives -cycle in the human heart and vessels at population scale.…”

Section: Discussionmentioning

confidence: 69%

A population-based human enCYCLOPedia for circadian medicine

Ruben

Smith

et al. 2018

Preprint

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One Sentence Summary: Bioinformatic analyses on thousands of human tissue samples reveals an enCYCLOPedia of rhythmic gene expression across the body and identifies key translational opportunities for circadian medicine in cardiovascular disease. Abstract:The discovery that half of the mammalian protein-coding genome is clock-regulated has clear implications for medicine. Indeed, recent studies demonstrate time-of-day impact on therapeutic outcomes in human heart disease and cancer. Yet biological time is rarely given clinical consideration. A key barrier is the absence of information on the what and where of molecular rhythms in the human body. Here, we have applied CYCLOPS, an algorithm designed to reconstruct sample order in the absence of time-of-day information, to the GTEx collection of 632 human donors contributing 4,292 RNA-seq samples from 13 distinct human tissue types. We identify rhythms in expression across the body that persist at the population-level. This includes a set of 'ubiquitous cyclers' comprised of well-established circadian clock factors but also many genes without prior circadian context. Among thousands of tissue-divergent rhythms, we discover a set of genes robustly oscillating in cardiovascular tissue, including key drug targets relevant to heart disease. These results also have implications for genetic studies where circadian variability may have masked genetic influence. It is our hope that the human enCYCLOPedia helps drive the translation of circadian biology into prospective clinical trials in cardiology and many other therapeutic areas.

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Section: Discussionmentioning

confidence: 69%

A population-based human enCYCLOPedia for circadian medicine

Ruben

Smith

et al. 2018

Preprint

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“…In atrial muscle, a circadian rhythm has been reported in K v 4.2 ( Kcnd2 ) 41,43,44 , KChIP2 ( Kcnip2 ) 41,44 , K v 1.5 ( Kcna5 ) 41,43 , TASK-1 (K2p3.1; Kcnk3 ) 41 , Cx40 ( Gja5 ) 45 and Cx43 ( Gja1 ) 45 . In ventricular muscle, a circadian rhythm has been reported in Na v 1.5 ( Scn5a ) 46 , Ca v 1.2 ( Cacna1c ) 47 , K v 4.2 ( Kcnd2 ) 41,43,48 , KChIP2 ( Kcnip2 ) 41,44 , K v 1.5 ( Kcna5 ) 41,43 , ERG (K v 11.1; Kcnh2 ) 48 , TASK-1 (K2p3.1; Kcnk3 ) 41 , Cx40 ( Gja5 ) 45 and Cx43 ( Gja1 ) 45 . Some circadian varying ion channels are common to the sinus node and the atrial or ventricular muscle: Na v 1.5 ( Scn5a ), K v 4.2 ( Kcnd2 ), K v 1.5 ( Kcna5 ), ERG (K v 11.1; Kcnh2 ) and TASK-1 (K2p3.1; Kcnk3 ).…”

Section: Discussionmentioning

confidence: 96%

Circadian control of intrinsic heart rate via a sinus node clock and the pacemaker channel

Wang

Olieslagers

Johnsen

et al. 2019

Preprint

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29In the human, there is a circadian rhythm in the resting heart rate and it is higher during the day in 30 preparation for physical activity. Conversely, slow heart rhythms (bradyarrhythmias) occur primarily 31 at night. Although the lower heart rate at night is widely assumed to be neural in origin (the result 32 of high vagal tone), the objective of the study was to test whether there is an intrinsic change in 33 heart rate driven by a local circadian clock. In the mouse, there was a circadian rhythm in the heart 34 rate in vivo in the conscious telemetrized animal, but there was also a circadian rhythm in the 35 intrinsic heart rate in denervated preparations: the Langendorff-perfused heart and isolated sinus 36 node. In the sinus node, experiments (qPCR and bioluminescence recordings in mice with a Per1 37 luciferase reporter) revealed functioning canonical clock genes, e.g. Bmal1 and Per1. We identified 38 a circadian rhythm in the expression of key ion channels, notably the pacemaker channel Hcn4 39 (mRNA and protein) and the corresponding ionic current (funny current, measured by whole cell 40 patch clamp in isolated sinus node cells). Block of funny current in the isolated sinus node 41 abolished the circadian rhythm in the intrinsic heart rate. Incapacitating the local clock (by cardiac-42 specific knockout of Bmal1) abolished the normal circadian rhythm of Hcn4, funny current and the 43 intrinsic heart rate. Chromatin immunoprecipitation demonstrated that Hcn4 is a transcriptional 44 target of BMAL1 establishing a pathway by which the local clock can regulate heart rate. In 45 conclusion, there is a circadian rhythm in the intrinsic heart rate as a result of a local circadian 46 clock in the sinus node that drives rhythmic expression of Hcn4. The data reveal a novel regulator 47 of heart rate and mechanistic insight into the occurrence of bradyarrhythmias at night. 483 Living things including humans are attuned to the 24 h day-night cycle and many biological 49 processes exhibit an intrinsic ~24 h (i.e. circadian) rhythm. In the human, the resting heart rate (in 50 the absence of physical activity) shows a circadian rhythm and is higher during the day when we 51 are awake 1,2 . The heart is therefore primed, anticipating the increase in demand during the awake 52 period. Conversely, bradyarrhythmias primarily occur at night 1,3 . Previously, the circadian rhythm in 53 heart rate in vivo has been attributed to the autonomic nervous system: to high sympathetic nerve 54 activity accompanying physical activity during the awake period and high vagal tone during the 55 sleep period 4 . This is partly based on heart rate variability as a surrogate measure of autonomic 56 tone 5-7 ; however, we have shown that heart rate variability cannot be used in any simple way as a 57 measure of autonomic tone 8 . Therefore, the mechanism underlying the circadian rhythm in heart 58 rate is still unknown. We asked the question whether there is a circadian rhythm in the intrinsic 59 heart rate set by the pacemaker of the he...

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“…All of the parameters for the potassium current, except the maximal conductance g K , were kept the same as in the Sato model: τ x = 300 ms, reversal potential E K = −80 mV, and activation kinetics θ x = −40 mV, σ x = −5 mV. For the calcium current, we set τ f = 80 ms as in the Sato model, and then fit the remaining parameters to the voltage-clamp data from Chen et al [9] shown in Figure 1A. In these recordings, Chen et al measured the L-type calcium current in cardiomyocytes isolated from guinea pigs housed under 12h:12h light:dark cycles, with the lights turned on at Zeitgeber time 0 (ZT0, 7:00 AM) and turned off at ZT12 (7:00 PM).…”

Section: Single-cell Modelmentioning

confidence: 99%

“…The effect of circadian variation in potassium current on action potential (AP) duration and QT interval has been studied using mathematical models of murine, guinea pig, and human myocytes [21,60]. Recent experiments in guinea pig myocytes have shown that L-type calcium current (I CaL ) is under circadian control as well, possibly through the PI3K-Akt signaling pathway [9]. How QT interval is affected by circadian oscillations in the concentration of sodium, potassium, and calcium ions in plasma was also studied in biophysically detailed models of human left ventricular cardiomyocytes [20].…”

Section: Introductionmentioning

confidence: 99%

Circadian rhythms of early afterdepolarizations and ventricular arrhythmias in a cardiomyocyte model

Diekman

Wei

2020

Preprint

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Sudden cardiac arrest is a malfunction of the heart's electrical system, typically caused by ventricular arrhythmias, that can lead to sudden cardiac death (SCD) within minutes. Epidemiological studies have shown that SCD and ventricular arrhythmias are more likely to occur in the morning than in the evening, and laboratory studies indicate that these daily rhythms in adverse cardiovascular events are at least partially under the control of the endogenous circadian timekeeping system. However, the biophysical mechanisms linking molecular circadian clocks to cardiac arrhythmogenesis are not fully understood. Recent experiments have shown that L-type calcium channels exhibit circadian rhythms in both expression and function in guinea pig ventricular cardiomyocytes. We developed an electrophysiological model of these cells to simulate the effect of circadian variation in L-type calcium conductance. We found that there is a circadian pattern in the occurrence of early afterdepolarizations (EADs), which are abnormal depolarizations during the repolarization phase of a cardiac action potential that can trigger fatal ventricular arrhythmias. Specifically, the model produces EADs in the morning but not at other times of day. We show that the model exhibits a codimension-2 Takens-Bogdanov bifurcation that serves as an organizing center for different types of EAD dynamics. We also simulated a 2-D spatial version of this model across a circadian cycle. We found that there is a circadian pattern in the breakup of spiral waves, which represents ventricular fibrillation in cardiac tissue. Specifically, the model produces spiral wave breakup in the morning but not in the evening. Our study is the first to propose a link between circadian rhythms and EAD formation and suggests that the efficacy of drugs targeting EAD-mediated arrhythmias may depend on the time of day that they are administered.

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CLOCK-BMAL1 regulate the cardiac L-type calcium channel subunit CACNA1C through PI3K-Akt signaling pathway

Cited by 31 publications

References 41 publications

A population-based human enCYCLOPedia for circadian medicine

A population-based human enCYCLOPedia for circadian medicine

Circadian control of intrinsic heart rate via a sinus node clock and the pacemaker channel

Circadian rhythms of early afterdepolarizations and ventricular arrhythmias in a cardiomyocyte model

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