scholarly journals Hypoxia induces a time- and tissue-specific response that elicits intertissue circadian clock misalignment

2019 ◽  
Vol 117 (1) ◽  
pp. 779-786 ◽  
Author(s):  
Gal Manella ◽  
Rona Aviram ◽  
Nityanand Bolshette ◽  
Sapir Muvkadi ◽  
Marina Golik ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Ex Vivo ◽  
Acute Hypoxia ◽  
Time Of Day ◽  
Chronic Obstructive ◽  
Specific Response ◽  
Dependent Manner ◽  
Tissue Specific ◽  
Circadian Misalignment ◽  
Obstructive Sleep

The occurrence and sequelae of disorders that lead to hypoxic spells such as asthma, chronic obstructive pulmonary disease, and obstructive sleep apnea (OSA) exhibit daily variance. This prompted us to examine the interaction between the hypoxic response and the circadian clock in vivo. We found that the global transcriptional response to acute hypoxia is tissue-specific and time-of-day–dependent. In particular, clock components differentially responded at the transcriptional and posttranscriptional level, and these responses depended on an intact circadian clock. Importantly, exposure to hypoxia phase-shifted clocks in a tissue-dependent manner led to intertissue circadian clock misalignment. This differential response relied on the intrinsic properties of each tissue and could be recapitulated ex vivo. Notably, circadian misalignment was also elicited by intermittent hypoxia, a widely used model for OSA. Given that phase coherence between circadian clocks is considered favorable, we propose that hypoxia leads to circadian misalignment, contributing to the pathophysiology of OSA and potentially other diseases that involve hypoxia.

scholarly journals Intermittent hypoxia-induced glucose intolerance is abolished by α-adrenergic blockade or adrenal medullectomy

2014 ◽  
Vol 307 (11) ◽  
pp. E1073-E1083 ◽  
Author(s):  
Jonathan C. Jun ◽  
Mi-Kyung Shin ◽  
Ronald Devera ◽  
Qiaoling Yao ◽  
Omar Mesarwi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Glucose Metabolism ◽  
Glucose Intolerance ◽  
Intermittent Hypoxia ◽  
Acute Hypoxia ◽  
Adrenergic Blockade ◽  
Dependent Manner ◽  
Obstructive Sleep ◽  
Dose Dependent

Obstructive sleep apnea causes intermittent hypoxia (IH) during sleep and is associated with dysregulation of glucose metabolism. We developed a novel model of clinically realistic IH in mice to test the hypothesis that IH causes hyperglycemia, glucose intolerance, and insulin resistance via activation of the sympathetic nervous system. Mice were exposed to acute hypoxia of graded severity (21, 14, 10, and 7% O2) or to IH of graded frequency [oxygen desaturation index (ODI) of 0, 15, 30, or 60, SpO2nadir 80%] for 30 min to measure levels of glucose fatty acids, glycerol, insulin, and lactate. Glucose tolerance tests and insulin tolerance tests were then performed under each hypoxia condition. Next, we examined these outcomes in mice that were administered phentolamine (α-adrenergic blockade) or propranolol (β-adrenergic blockade) or that underwent adrenal medullectomy before IH exposure. In all experiments, mice were maintained in a thermoneutral environment. Sustained and IH induced hyperglycemia, glucose intolerance, and insulin resistance in a dose-dependent fashion. Only severe hypoxia (7% O2) increased lactate, and only frequent IH (ODI 60) increased plasma fatty acids. Phentolamine or adrenal medullectomy both prevented IH-induced hyperglycemia and glucose intolerance. IH inhibited glucose-stimulated insulin secretion, and phentolamine prevented the inhibition. Propranolol had no effect on glucose metabolism but abolished IH-induced lipolysis. IH-induced insulin resistance was not affected by any intervention. Acutely hypoxia causes hyperglycemia, glucose intolerance, and insulin resistance in a dose-dependent manner. During IH, circulating catecholamines act upon α-adrenoreceptors to cause hyperglycemia and glucose intolerance.

scholarly journals Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome

2018 ◽  
Vol 115 (23) ◽  
pp. E5390-E5399 ◽  
Author(s):  
Christopher M. Depner ◽  
Edward L. Melanson ◽  
Andrew W. McHill ◽  
Kenneth P. Wright
Keyword(s):  
Food Intake ◽  
Circadian Clock ◽  
Human Plasma ◽  
Plasma Proteins ◽  
Time Of Day ◽  
Great Promise ◽  
Plasma Proteome ◽  
Circadian Misalignment ◽  
Altered Proteins ◽  
Nighttime Sleep

Proteomics holds great promise for understanding human physiology, developing health biomarkers, and precision medicine. However, how much the plasma proteome varies with time of day and is regulated by the master circadian suprachiasmatic nucleus brain clock, assessed here by the melatonin rhythm, is largely unknown. Here, we assessed 24-h time-of-day patterns of human plasma proteins in six healthy men during daytime food intake and nighttime sleep in phase with the endogenous circadian clock (i.e., circadian alignment) versus daytime sleep and nighttime food intake out of phase with the endogenous circadian clock (i.e., circadian misalignment induced by simulated nightshift work). We identified 24-h time-of-day patterns in 573 of 1,129 proteins analyzed, with 30 proteins showing strong regulation by the circadian cycle. Relative to circadian alignment, the average abundance and/or 24-h time-of-day patterns of 127 proteins were altered during circadian misalignment. Altered proteins were associated with biological pathways involved in immune function, metabolism, and cancer. Of the 30 circadian-regulated proteins, the majority peaked between 1400 hours and 2100 hours, and these 30 proteins were associated with basic pathways involved in extracellular matrix organization, tyrosine kinase signaling, and signaling by receptor tyrosine-protein kinase erbB-2. Furthermore, circadian misalignment altered multiple proteins known to regulate glucose homeostasis and/or energy metabolism, with implications for altered metabolic physiology. Our findings demonstrate the circadian clock, the behavioral wake–sleep/food intake–fasting cycle, and interactions between these processes regulate 24-h time-of-day patterns of human plasma proteins and help identify mechanisms of circadian misalignment that may contribute to metabolic dysregulation.

scholarly journals Time of Day Regulates Renal Mineralocorticoid Receptor Transcriptional Control of Electrolyte Balance

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A819-A820
Author(s):  
Monica Kanki ◽  
James Morgan ◽  
Peter J Fuller ◽  
Morag Jennifer Young
Keyword(s):  
Circadian Clock ◽  
Mineralocorticoid Receptor ◽  
Target Genes ◽  
Clock Genes ◽  
Rest Period ◽  
Time Of Day ◽  
Cardiac Cells ◽  
Electrolyte Balance ◽  
Dependent Manner ◽  
Peripheral Tissues

Abstract The mineralocorticoid receptor (MR) has an established role in blood pressure control and cardiovascular homeostasis via many actions in the heart and kidney. We recently identified a role for the MR in controlling the circadian clock in cardiac cells and demonstrated that time-of-day impacts MR activation in the heart. While time dependent behaviours such as upright posture and fluid intake control aldosterone release via the renin-angiotensin-aldosterone system (RAAS), we hypothesise that the circadian clock controls aldosterone signalling by modifying MR transcriptional outcomes. Two established MR target genes and core circadian clock genes are period 1 (Per1) and period 2 (Per2). We have previously shown that a bolus dose of aldosterone (i.p.) induced cardiac expression of Per1 and Per2 in wildtype mice treated at 8AM (start of rest period) but not when administered at 8PM (start of active period). Whether MR activation in the kidney is similarly dependent on time of day and aligns with MR actions in the heart remains to be assessed. We also sought to determine if the MR directly regulates the molecular clock in a ligand-dependent manner. In contrast to the heart, renal Per1 and Per2 expression was not upregulated at four hours following aldosterone administration at either 8AM or 8PM. Interestingly, aldosterone administered at 8AM, but not at 8PM, significantly down-regulated expression of the circadian clock gene, nuclear receptor reverse strand c-ERBA (ReverbA); ReverbA was not regulated in the heart following aldosterone treatment. Investigation of renal-MR target genes involved in sodium ion transfer, showed a down-regulation of epithelial sodium channel 1 alpha (ENaC-α), by aldosterone administered only at 8AM. Conversely, aldosterone administered at 8AM induced gene expression of FKBP Prolyl Isomerase 5 (Fkbp5), an immunophilin that is important in nuclear trafficking of the MR. These data provide new insights for tissue sensitivity to MR activation in the heart and the kidney, which may play differing roles in contributing to regulating circadian patterns of several cardiovascular and renal parameters. Moreover, our data suggest that in addition to the accepted entrainment role of the glucocorticoid receptor (GR), the MR may also play a role in the entrainment of the circadian clock in peripheral tissues. Ongoing mechanistic studies will determine whether the MR can directly control the periodicity of the renal cellular clock, as it does in the heart. Key outcomes will be assessed in population databases to determine the clinical relevance of these findings. We propose that understanding of time-of-day dependent vulnerability to MR signalling in the heart versus the kidney may offer the rationale for the development of novel temporal or tissue specific-MR modulators in the management of cardiovascular disease.

scholarly journals Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation

2015 ◽  
Vol 309 (11) ◽  
pp. H1827-H1836 ◽  
Author(s):  
Kevin A. Ingle ◽  
Vasundhara Kain ◽  
Mehak Goel ◽  
Sumanth D. Prabhu ◽  
Martin E. Young ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Circadian Clock ◽  
Diastolic Dysfunction ◽  
Expression Profiles ◽  
Systolic Dysfunction ◽  
Time Of Day ◽  
Mouse Heart ◽  
Dependent Manner ◽  
Resolution Of Inflammation ◽  
Ecm Remodeling

The mammalian circadian clock consists of multiple transcriptional regulators that coordinate biological processes in a time-of-day-dependent manner. Cardiomyocyte-specific deletion of the circadian clock component, Bmal1 (aryl hydrocarbon receptor nuclear translocator-like protein 1), leads to age-dependent dilated cardiomyopathy and decreased lifespan in mice. We investigated whether cardiomyocyte-specific Bmal1 knockout (CBK) mice display early alterations in cardiac diastolic function, extracellular matrix (ECM) remodeling, and inflammation modulators by investigating CBK mice and littermate controls at 8 and 28 wk of age (i.e., prior to overt systolic dysfunction). Left ventricles of CBK mice exhibited ( P < 0.05): 1) progressive abnormal diastolic septal annular wall motion and reduced pulmonary venous flow only at 28 wk of age; 2) progressive worsening of fibrosis in the interstitial and endocardial regions from 8 to 28 wk of age; 3) increased (>1.5 fold) expression of collagen I and III, as well as the matrix metalloproteinases MMP-9, MMP-13, and MMP-14 at 28 wk of age; 4) increased transcript levels of neutrophil chemotaxis and leukocyte migration genes ( Ccl2, Ccl8, Cxcl2, Cxcl1, Cxcr2, Il1β) with no change in Il-10 and Il-13 genes expression; and 5) decreased levels of 5-LOX, HO-1 and COX-2, enzymes indicating impaired resolution of inflammation. In conclusion, genetic disruption of the cardiomyocyte circadian clock results in diastolic dysfunction, adverse ECM remodeling, and proinflammatory gene expression profiles in the mouse heart, indicating signs of early cardiac aging in CBK mice.

scholarly journals The rat cerebral vasculature exhibits time-of-day-dependent oscillations in circadian clock genes and vascular function that are attenuated following obstructive sleep apnea

2016 ◽  
Vol 37 (8) ◽  
pp. 2806-2819 ◽  
Author(s):  
David J Durgan ◽  
Randy F Crossland ◽  
Robert M Bryan
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Circadian Clock ◽  
Diurnal Rhythm ◽  
Vascular Function ◽  
Clock Genes ◽  
Cerebral Arteries ◽  
Active Phase ◽  
Time Of Day ◽  
Obstructive Sleep

Circadian clock components oscillate in cells of the cardiovascular system. Disruption of these oscillations has been observed in cardiovascular diseases. We hypothesized that obstructive sleep apnea, which is associated with cerebrovascular diseases, disrupts the cerebrovascular circadian clock and rhythms in vascular function. Apneas were produced in rats during sleep. Following two weeks of sham or obstructive sleep apnea, cerebral arteries were isolated over 24 h for mRNA and functional analysis. mRNA expression of clock genes exhibited 24-h rhythms in cerebral arteries of sham rats (p < 0.05). Interestingly, peak expression of clock genes was significantly lower following obstructive sleep apnea (p < 0.05). Obstructive sleep apnea did not alter clock genes in the heart, or rhythms in locomotor activity. Isolated posterior cerebral arteries from sham rats exhibited a diurnal rhythm in sensitivity to luminally applied ATP, being most responsive at the beginning of the active phase (p < 0.05). This rhythm was absent in arteries from obstructive sleep apnea rats (p < 0.05). Rhythms in ATP sensitivity in sham vessels were absent, and not different from obstructive sleep apnea, following treatment with L-NAME and indomethacin. We conclude that cerebral arteries possess a functional circadian clock and exhibit a diurnal rhythm in vasoreactivity to ATP. Obstructive sleep apnea attenuates these rhythms in cerebral arteries, potentially contributing to obstructive sleep apnea-associated cerebrovascular disease.

scholarly journals Circadian asthma airway responses are gated by REV-ERBα

2020 ◽  
pp. 1902407
Author(s):  
Hannah J. Durrington ◽  
Karolina Krakowiak ◽  
Peter Meijer ◽  
Nicola Begley ◽  
Robert Maidstone ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Airway Hyperresponsiveness ◽  
Ex Vivo ◽  
Allergen Challenge ◽  
Active Phase ◽  
Time Of Day ◽  
Receptor Expression ◽  
Dominant Feature ◽  
Clock Protein

BackgroundAsthma is an inflammatory disease of the airway showing a strong time of day rhythm. Airway hyperresponsiveness is a dominant feature of asthma, but it is not known if this is under clock control. The circadian clock powerfully regulates inflammation. The clock protein REV-ERBα is known to play a key role as a repressor of the inflammatory response.ObjectivesTo determine if allergy mediated airway hyperresponsiveness is gated by the clock protein, REV-ERBα.MethodsAfter exposure to the intra-nasal house dust mite allergen challenge model at either dawn or dusk, airway hyper-responsiveness to methacholine was measured invasively in mice.Main ResultsWild-type mice showed marked time-of-day differential responses of airway hyper-responsiveness (maximal at dusk, start of the active phase), both in vivo and ex vivo in precision cut lung slices. Hyper-responsive time of day effects were abolished in mice lacking the clock gene Rev-erbα, indicating that time-of-day effects on asthma responses are likely mediated via the circadian clock. We suggest that muscarinic receptors 1 and 3 (Chrm 1, 3) may play a role in this pathway.ConclusionsWe identify a novel circuit regulating a core process in asthma, potentially involving circadian control of muscarinic receptor expression, in a REV-ERBα dependent fashion.Clinical ImplicationThese insights suggest the importance of considering timing of drug administration in clinic trials, and in clinical practice; chronotherapy.

A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine

2018 ◽  
Vol 10 (458) ◽  
pp. eaat8806 ◽  
Author(s):  
Marc D. Ruben ◽  
Gang Wu ◽  
David F. Smith ◽  
Robert E. Schmidt ◽  
Lauren J. Francey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Drug Targets ◽  
Time Of Day ◽  
The Body ◽  
Protein Coding ◽  
Tissue Specific ◽  
Biological Time ◽  
Potential Applications ◽  
Key Barrier

The discovery that half of the mammalian protein-coding genome is regulated by the circadian clock has clear implications for medicine. Recent studies demonstrated that the circadian clock influences therapeutic outcomes in human heart disease and cancer. However, biological time is rarely given clinical consideration. A key barrier is the absence of information on tissue-specific molecular rhythms in the human body. We have applied the cyclic ordering by periodic structure (CYCLOPS) algorithm, designed to reconstruct sample temporal order in the absence of time-of-day information, to the gene expression collection of 13 tissues from 632 human donors. We identified rhythms in gene expression across the body; nearly half of protein-coding genes were shown to be cycling in at least 1 of the 13 tissues analyzed. One thousand of these cycling genes encode proteins that either transport or metabolize drugs or are themselves drug targets. These results provide a useful resource for studying the role of circadian rhythms in medicine and support the idea that biological time might play a role in determining drug response.

scholarly journals The influence of the gut microbiome on BCG-induced trained immunity

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Martin Stražar ◽  
Vera P. Mourits ◽  
Valerie A. C. M. Koeken ◽  
L. Charlotte J. de Bree ◽  
Simone J. C. F. M. Moorlag ◽  
...  
Keyword(s):  
Immune Responses ◽  
Gut Microbiome ◽  
De Novo ◽  
Ex Vivo ◽  
Specific Response ◽  
Dependent Manner ◽  
De Novo Genome Assembly ◽  
Bcg Vaccination ◽  
Vaccine Responses ◽  
Phenylalanine Metabolism

Abstract Background The bacillus Calmette-Guérin (BCG) vaccine protects against tuberculosis and heterologous infections but elicits high inter-individual variation in specific and nonspecific, or trained, immune responses. While the gut microbiome is increasingly recognized as an important modulator of vaccine responses and immunity in general, its potential role in BCG-induced protection is largely unknown. Results Stool and blood were collected from 321 healthy adults before BCG vaccination, followed by blood sampling after 2 weeks and 3 months. Metagenomics based on de novo genome assembly reveals 43 immunomodulatory taxa. The nonspecific, trained immune response is detected by altered production of cytokines IL-6, IL-1β, and TNF-α upon ex vivo blood restimulation with Staphylococcus aureus and negatively correlates with abundance of Roseburia. The specific response, measured by IFN-γ production upon Mycobacterium tuberculosis stimulation, is associated positively with Ruminococcus and Eggerthella lenta. The identified immunomodulatory taxa also have the strongest effects on circulating metabolites, with Roseburia affecting phenylalanine metabolism. This is corroborated by abundances of relevant enzymes, suggesting alternate phenylalanine metabolism modules are activated in a Roseburia species-dependent manner. Conclusions Variability in cytokine production after BCG vaccination is associated with the abundance of microbial genomes, which in turn affect or produce metabolites in circulation. Roseburia is found to alter both trained immune responses and phenylalanine metabolism, revealing microbes and microbial products that may alter BCG-induced immunity. Together, our findings contribute to the understanding of specific and trained immune responses after BCG vaccination.

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