Abstract 430: Circadian Control of Heart Rate

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Alicia D’souza ◽  
Sven Wegner ◽  
Anne Berit Johnsen ◽  
Eleanor Gill ◽  
Charlotte Cox ◽  
...  
Keyword(s):  
Heart Rate ◽  
Transcription Factors ◽  
Circadian Rhythm ◽  
Ion Channels ◽  
Circadian Rhythms ◽  
Ion Channel ◽  
Circadian Clock ◽  
Alternative Hypothesis ◽  
Cardiac Pacemaker ◽  
Upstream Region

Background: Bradyarrhythmias occur more frequently at night. On the basis of heart rate variability this is attributed to high vagal tone. Here we tested the alternative hypothesis that an intrinsic circadian clock-driven remodelling of pacemaking ion channels underlies fluctuations in heart rate (HR). Methods and results: The occurrence of a circadian rhythm in HR was tested by placing nocturnal C57BL6/J mice under a strict 12/12h light-dark cycle and telemetry-based ECG intervals measured every 2 h for 48 h. Under these conditions, the R-R interval was rhythmic (n=10). To test whether this is caused by circadian rhythms in the expression of ion channels controlling HR, sinus node (SAN) biopsies were collected at time points corresponding to the minima (ZT0, subjective day) and maxima (ZT12, subjective night) of HR, as determined by ECG recordings. Real-time PCR normalised to 28s demonstrated an elevated expression of the key pacemaking ion channel HCN4 that carries the pacemaker current I f and genes encoding the Ca 2+ -handling proteins SERCA2a and RYR2 at ZT12 ( P <0.05, n=10). Presence of clock machinery (essential transcription factors involved in setting intrinsic circadian rhythms) as potential regulators of ion channel oscillation were investigated in the SAN of mPer1 Luc mice which carry the 5’ upstream region of the mPer1 gene (a key core clock component) fused to a luciferase gene. mPer1-luc bioluminescence was recorded in the isolated SAN using a light-tight photomultiplier tube assembly to reveal a circadian rhythm with a periodicity of 24 h (n=3). Disruption of the molecular clock by global knockout of core clock components Cry1 and Cry2 abrogated the circadian cycling of mPer1-luc in the SN of Cry1 -/- /Cry2 -/- double knockout mice (n=3). Examination of 10[[Unable to Display Character: &#8201;]]kb of the Hcn4 promoter revealed a conserved consensus binding site for CLOCK and its heterodimer BMAL1, other essential transcription factors involved in setting intrinsic circadian rhythms. Conclusions: This is the first demonstration of a peripheral circadian clock in the cardiac pacemaker and circadian oscillations in key pacemaker mechanisms. Data reveal a novel regulator of SN function and the occurrence of bradyarrythmias at night.

scholarly journals Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

2021 ◽  
Vol 22 (2) ◽  
pp. 676
Author(s):  
Andy W. C. Man ◽  
Huige Li ◽  
Ning Xia
Keyword(s):  
Circadian Rhythm ◽  
Cardiovascular Diseases ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Therapeutic Target ◽  
Environmental Changes ◽  
Clock Genes ◽  
Vascular System ◽  
Peripheral Tissues ◽  
Inflammatory Processes

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock.

scholarly journals MON-015 Pregnancy Adapts Circadian Rhythms in the Reproductive Axis: Impact on Labor Regulating Drug Efficacy

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Hanne Mette Hoffmann ◽  
Thu V Duong ◽  
Duong Nguyen ◽  
Asad Muhammed ◽  
Alexandra M Yaw
Keyword(s):  
Transcription Factors ◽  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Ex Vivo ◽  
Drug Efficacy ◽  
Time Of Day ◽  
Receptor Expression ◽  
Behavioral Activity ◽  
Reproductive Tissues ◽  
Reproductive Axis

Abstract Molecular and behavioral timekeeping is regulated by the circadian system represented on the cellular level by clock transcription factors, including Period2 (PER2), Bmal1, Clock and Cry. These transcription factors drive a daily ~24h rhythm in gene expression leading to tissue specific receptor expression optimizing sensitivity to hormones and drugs dependent on the time of day. To synchronize circadian rhythms in the body to the time of day, the brain’s suprachiasmatic nucleus (SCN) translates environmental light information into neuronal and endocrine signals allowing circadian rhythm synchrony. Despite the critical role of circadian rhythms in fertility, it remains unknown how circadian rhythms change within reproductive tissues during pregnancy, and how these adaptations might impact drug efficacy. Monitoring wheel-running patterns in circadian PER2::luciferase (PER2::LUC) reporter mice, we confirmed that pregnancy is associated with reductions of activity and identified a correlation between delayed onset of behavioral activity during late pregnancy and ex vivo SCN PER2::LUC period, whereas no correlation between arcuate nucleus PER2::LUC rhythms was identified. The time of day of peak PER2::LUC expression provides a time-stamp as to the circadian phase of a tissue. Pregnancy impacted circadian synchrony in the reproductive axis, with the most dramatic change within the uterus. To understand how circadian rhythms responded to input during pregnancy, we performed a pharmacology study and found that circadian rhythm generation in the uterus responded differentially to hormones regulating pregnancy and labor depending on gestational age and the time of day of drug administration. To test for functional changes in uterine contraction capacity, we recorded ex vivo uterine contractions. Our preliminary data reveal a circadian change in uterine function in the mouse, which impacted labor regulating drug efficacy depending on the time of day. Together our data show that pregnancy is associated with behavioral changes in locomotor activity patterns, as well as adaptations in phase-relationships in reproductive tissues. Our chrono-pharmacology study indicates that a better understanding of labor-regulating drug efficacy can potentially allow increased efficacy of currently used drugs in the clinic to both induce labor as well as halt preterm labor.

scholarly journals Roles of Neuropeptides, VIP and AVP, in the Mammalian Central Circadian Clock

2021 ◽  
Vol 15 ◽  
Author(s):  
Daisuke Ono ◽  
Ken-ichi Honma ◽  
Sato Honma
Keyword(s):  
Transcription Factors ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Cellular Networks ◽  
Clock Genes ◽  
Circadian System ◽  
Developmental Changes ◽  
Circadian Period ◽  
Functional Roles ◽  
Environmental Light

In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Individual SCN cells exhibit intrinsic oscillations, and their circadian period and robustness are different cell by cell in the absence of cellular coupling, indicating that cellular coupling is important for coherent circadian rhythms in the SCN. Several neuropeptides such as arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) are expressed in the SCN, where these neuropeptides function as synchronizers and are important for entrainment to environmental light and for determining the circadian period. These neuropeptides are also related to developmental changes of the circadian system of the SCN. Transcription factors are required for the formation of neuropeptide-related neuronal networks. Although VIP is critical for synchrony of circadian rhythms in the neonatal SCN, it is not required for synchrony in the embryonic SCN. During postnatal development, the clock genes cryptochrome (Cry)1 and Cry2 are involved in the maturation of cellular networks, and AVP is involved in SCN networks. This mini-review focuses on the functional roles of neuropeptides in the SCN based on recent findings in the literature.

Minimally Invasive Ways of Determining Circadian Rhythms in Humans

Physiology ◽  
2021 ◽  
Vol 36 (1) ◽  
pp. 7-20 ◽  
Author(s):  
Sandra Crnko ◽  
Hilde Schutte ◽  
Pieter A. Doevendans ◽  
Joost P. G. Sluijter ◽  
Linda W. van Laake
Keyword(s):  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Minimally Invasive ◽  
Circadian Clock ◽  
Critical Role ◽  
Health And Disease

Circadian rhythm exerts a critical role in mammalian health and disease. A malfunctioning circadian clock can be a consequence, as well as the cause of several pathophysiologies. Clinical therapies and research may also be influenced by the clock. Since the most suitable manner of revealing this rhythm in humans is not yet established, we discuss existing methods and seek to determine the most feasible ones.

scholarly journals Role of mutation of the circadian clock gene Per2 in cardiovascular circadian rhythms

2010 ◽  
Vol 298 (3) ◽  
pp. R627-R634 ◽  
Author(s):  
Ana Vukolic ◽  
Vladan Antic ◽  
Bruce N. Van Vliet ◽  
Zhihong Yang ◽  
Urs Albrecht ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Locomotor Activity ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Mutant Mice ◽  
Constant Darkness ◽  
Wild Type ◽  
Chi Square ◽  
Dark Light

Alterations in the circadian blood pressure pattern are frequently observed in hypertension and lead to increased cardiovascular morbidity. However, there are no studies that have investigated a possible implication of the Period2 gene, a key component of the molecular circadian clock, on the circadian rhythms of blood pressure and heart rate. To address this question, we monitored blood pressure, heart rate, and locomotor activity 24 h a day by telemetry in mice carrying a mutation in the Period2 gene and in wild-type control mice. Under a standard 12:12-h light-dark cycle, mutant mice showed a mild cardiovascular phenotype with an elevated 24-h heart rate, a decreased 24-h diastolic blood pressure, and an attenuation of the dark-light difference in blood pressure and heart rate. Locomotor activity was similar in both groups and did not appear to explain the observed hemodynamic differences. When mice were placed under constant darkness during eight consecutive days, wild-type mice maintained 24-h rhythms, whereas there was an apparent progressive loss of 24-h rhythm of blood pressure, heart rate, and locomotor activity in mutant mice. However, a chi square periodogram revealed that circadian rhythms were preserved under complete absence of any light cue, but with shorter periods by ∼40 min, leading to a cumulative phase shift toward earlier times of ∼5 h and 20 min by the end of the 8th day. When heart rate, mean arterial pressure, and activity were recalculated according to the endogenous circadian periods of each individual mouse, the amplitudes of the circadian rhythms (“subjective night”-“subjective day” differences) were maintained for all variables studied. Our data show that mutation of the Period2 gene results in an attenuated dipping of blood pressure and heart rate during both light-dark cycles and constant darkness, and in shorter circadian periods during constant darkness.

scholarly journals Mechanistic Insights Into the Reduced Pacemaking Rate of the Rabbit Sinoatrial Node During Postnatal Development: A Simulation Study

2020 ◽  
Vol 11 ◽  
Author(s):  
Azzah M. Alghamdi ◽  
Craig P. Testrow ◽  
Dominic G. Whittaker ◽  
Mark R. Boyett ◽  
Jules. C. Hancox ◽  
...  
Keyword(s):  
Heart Rate ◽  
Ion Channels ◽  
Ion Channel ◽  
Postnatal Development ◽  
Sinoatrial Node ◽  
Cell Model ◽  
Underlying Mechanism ◽  
Biophysical Modeling ◽  
Cellular Mechanisms ◽  
Rabbit Sinoatrial Node

Marked age- and development- related differences have been observed in morphology and characteristics of action potentials (AP) of neonatal and adult sinoatrial node (SAN) cells. These may be attributable to a different set of ion channel interactions between the different ages. However, the underlying mechanism(s) have yet to be elucidated. The objective of this study was to determine the mechanisms underlying different spontaneous APs and heart rate between neonatal and adult SAN cells of the rabbit heart by biophysical modeling approaches. A mathematical model of neonatal rabbit SAN cells was developed by modifying the current densities and/or kinetics of ion channels and transporters in an adult cell model based on available experimental data obtained from neonatal SAN cells. The single cell models were then incorporated into a multi-cellular, two-dimensional model of the intact SAN-atrium to investigate the functional impact of altered ion channels during maturation on pacemaking electrical activities and their conduction at the tissue level. Effects of the neurotransmitter acetylcholine on the pacemaking activities in neonatal cells were also investigated and compared to those in the adult. Our results showed: (1) the differences in ion channel properties between neonatal and adult SAN cells are able to account for differences in their APs and the heart rate, providing mechanistic insight into understanding the reduced pacemaking rate of the rabbit sinoatrial node during postnatal development; (2) in the 2D model of the intact SAN-atria, it was shown that cellular changes during postnatal development impaired pacemaking activity through increasing the activation time and reducing the conduction velocity across the SAN; (3) the neonatal SAN model, with its faster beating rates, showed a greater sensitivity to parasympathetic modulation in response to acetylcholine than did the adult model. These results provide novel insights into the understanding of the cellular mechanisms underlying the differences in the cardiac pacemaking activities of the neonatal and adult SAN.

scholarly journals Circadian rhythm and neurodegenerative disorders

2020 ◽  
Vol 6 (2) ◽  
pp. 71-80
Author(s):  
Michelle Werdann ◽  
Yong Zhang
Keyword(s):  
Circadian Rhythm ◽  
Early Intervention ◽  
Circadian Rhythms ◽  
Neurodegenerative Diseases ◽  
Circadian Clock ◽  
Neurodegenerative Disorders ◽  
Circadian Clocks ◽  
Daily Rhythms ◽  
Animal Physiology ◽  
And Behavior

The circadian clock controls daily rhythms in animal physiology, metabolism, and behavior, such as the sleep‐wake cycle. Disruption of circadian rhythms has been revealed in many diseases including neurodegenerative disorders. Interestingly, patients with many neurodegenerative diseases often show problems with circadian clocks even years before other symptoms develop. Here we review the recent studies identifying the association between circadian rhythms and several major neurodegenerative disorders. Early intervention of circadian rhythms may benefit the treatment of neurodegeneration.

scholarly journals Simulated Space Environmental Factors of Weightlessness, Noise and Low Air Pressure Differentially Affect the Circadian Rhythm and Gut Microbiome

2021 ◽  
Author(s):  
Huan Ma ◽  
Xihui Gan ◽  
Jianwei Zhao ◽  
Yin Zhang ◽  
Silin Li ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Community Structure ◽  
Circadian Rhythms ◽  
Environmental Factors ◽  
Circadian Clock ◽  
Gut Microbiome ◽  
Atmospheric Pressure ◽  
Clock Genes ◽  
Low Atmospheric Pressure ◽  
Space Capsule

Abstract Backgroundhe circadian clock extensively regulates physiology and behavior. In space, the astronauts encounter many environmental factors that are dramatically different from those on earth, however, the effects of these factors on circadian rhythms and the mechanisms remain largely unknown. The present study aimed to investigate the changes in the mouse circadian rhythm and gut microbiome under simulated space capsule conditions, including microgravity, noise and low atmospheric pressure.ResultsNoise and low atmospheric pressure were loaded in the capsule while the conditions in the animal room remained constant. The mice in the capsule showed disturbed locomotor rhythms and faster adaptation to a 6-h phase advance. RNA sequencing of hypothalamus samples revealed that microgravity simulated by hind limb unloading (HU) and exposure to noise and low atmospheric pressure led to decreases in the quantities of differentially expressed genes (DEGs), including circadian clock genes. Changes in the rhythmicity of genes implicated in pathways of cardiovascular deconditioning and more concentrated circadian phases were found under HU or noise and low atmospheric pressure. Furthermore, 16S rRNA sequencing revealed dysbiosis in the gut microbiome, and noise and low atmospheric pressure may repress the temporal discrepancy in the microbiome community structure induced by microgravity. Changes in diel oscillation were observed in a number of gut bacteria with critical physiological consequences in metabolism and immunodefense.ConclusionsOur data demonstrate that in addition to microgravity, exposure to noise and low atmospheric pressure affect the robustness of circadian rhythms and the community structure of the gut microbiome, and these factors may interfere with each other in their adaptation to respective conditions. These findings are important to further our understanding of the alteration of circadian rhythms in the space complex environment.

scholarly journals Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer’s disease and longevity in an Italian population

GeroScience ◽  
2021 ◽  
Author(s):  
Maria Giulia Bacalini ◽  
Flavia Palombo ◽  
Paolo Garagnani ◽  
Cristina Giuliani ◽  
Claudio Fiorini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Successful Aging ◽  
Clock Genes ◽  
Association Studies ◽  
Italian Population ◽  
Age Related

AbstractMany physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant “zeitgeber” able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.

scholarly journals Mitogen-activated protein kinase p38 modulates pacemaker ion channels differentiation in P19-derived pluripotent cells

2020 ◽  
Vol 70 (1) ◽  
Author(s):  
Mingqi Zheng ◽  
Lin Kang ◽  
Tomoko Uchino ◽  
Gang Liu ◽  
Yan Wang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Ion Channels ◽  
Map Kinase ◽  
Kinase Inhibitor ◽  
Cardiac Pacemaker ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Pluripotent Cells ◽  
Intracellular Signals ◽  
Mitogen Activated Protein

Abstract Signal regulators during early cardiogenetic differentiation for the cellular automaticity are largely unknown. Our investigations were designed to clarify the role of transcription factors and their modulators in P19-derived cardiomyocytes to the expression of cardiac pacemaker ion channels. Transcription factors Csx/Nkx2.5 and GATA4 but not MEF2C were markedly inhibited by p38 MAP kinase inhibition in a distinct manner; expression but not phosphorylation of GATA4 was reduced by inhibition of p38 MAP kinase actions. In the presence of an ERK1/2,5 inhibitor PD98059 or a JNK MAP kinase inhibitor SP600125, P19 cells successfully differentiated into cardiomyocytes displaying spontaneous beatings with expression of three types of pacemaker ion channels. We demonstrate that acquisition of cellular automaticity and the expression of pacemaker ion channels are regulated by the transcription factors, Csx/Nkx2.5 and GATA4, through intracellular signals including p38 MAP kinase in the process of P19-derived pluripotent cells differentiation into cardiomyocytes.

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