Circadian-Hypoxia Link and its Potential for Treatment of Cardiovascular Disease

Bartman, Colleen M.; Eckle, Tobias

doi:10.2174/1381612825666190516081612

Cited by 23 publications

(24 citation statements)

References 210 publications

(266 reference statements)

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“…This potential interaction is supported by other studies proposing that there is a crosstalk between hypoxia response and regulation of circadian rhythm, demonstrating that both PER1 and BMAL1 interact with HIF1α, driving the transcription of common target genes [35][36][37]. Interestingly, HIF1α belongs to the same protein family as the core circadian proteins, the PAS domain superfamily of signal sensors for oxygen, light and metabolism [38,39]. PAS domains in PER proteins from circadian rhythm were found.…”

Section: Discussionsupporting

confidence: 66%

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SMAD4 Overexpression in Patients with Sleep Apnoea May Be Associated with Cardiometabolic Comorbidities

Díaz‐García

Oriol

Casitas

et al. 2020

JCM

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Obstructive sleep apnoea (OSA) is associated with several diseases related to metabolic and cardiovascular risk. Although the mechanisms involved in the development of these disorders may vary, OSA patients frequently present an increase in transforming growth factor beta (TGFβ), the activity of which is higher still in patients with hypertension, diabetes or cardiovascular morbidity. Smad4 is a member of the small mother against decapentaplegic homologue (Smad) family of signal transducers and acts as a central mediator of TGFβ signalling pathways. In this study, we evaluate Smad4 protein and mRNA expression from 52 newly diagnosed OSA patients, with an apnoea–hypopnoea index (AHI) ≥30 and 26 healthy volunteers. These analyses reveal that OSA patients exhibit high levels of SMAD4 which correlates with variation in HIF1α, mTOR and circadian genes. Moreover, we associated high concentrations of Smad4 plasma protein with the presence of diabetes, dyslipidaemia and hypertension in these patients. Results suggest that increased levels of SMAD4, mediated by intermittent hypoxaemia and circadian rhythm deregulation, may be associated with cardiometabolic comorbidities in patients with sleep apnoea.

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Section: Discussionsupporting

confidence: 66%

“…PAS domains in PER proteins from circadian rhythm were found. The PAS domains shared between PER and HIF1a suggest their functions may be similar [39]. Moreover, there is solid evidence from in vitro assays to support the crosslink between circadian and HIF pathways [40].…”

Section: Discussionmentioning

confidence: 99%

SMAD4 Overexpression in Patients with Sleep Apnoea May Be Associated with Cardiometabolic Comorbidities

Díaz‐García

Oriol

Casitas

et al. 2020

JCM

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“…Binding of HIF-1α to promoter regions of core clock genes at the genome level was also reported for mammalian cells (Peek et al 2016;Wu et al 2016). As recently reviewed (Bartman and Eckle 2019;Morgan et al 2019), the regulation of Period genes through Hif-1α is currently commonly accepted. Only recently, CRY1, but not CRY2, was identified as a negative regulator of HIF-1α in the mouse fibroblast NIH3-T3 and MEF cell lines, at the level of transactivation capacity, as well as at the level of protein quantity (Dimova et al 2019).…”

Section: Discussionmentioning

confidence: 88%

Therapeutic Nuclear Magnetic Resonance affects the core clock mechanism and associated Hypoxia-inducible factor-1

Thöni

Oliva

Mauracher

et al. 2021

Chronobiology International

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The influence of low intensity electromagnetic fields on circadian clocks of cells and tissues has gained increasing scientific interest, either as a therapeutic tool or as a potential environmental hazard. Nuclear Magnetic Resonance (NMR) refers to the property of certain atomic nuclei to absorb the energy of radio waves under a corresponding magnetic field. NMR forms the basis for Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy and, in a low-intensity form, for NMR therapy (tNMR). Since the circadian clock is bi-directionally intertwined with hypoxic signaling in vertebrates and mammals, we hypothesized that low intensity electromagnetic fields, such as tNMR, might not only affect circadian clocks but also Hypoxia-Inducible Factor-1α (HIF-1α). As master regulator of the hypoxic signaling pathway, HIF-1α is known to dampen the circadian amplitude under reduced oxygen availability, while the hypoxic response of cells and organisms, itself, is tightly clock controlled. In a first experiment, we investigated if tNMR is able to act as Zeitgeber for the core clock mechanism of unsynchronized zebrafish and mouse fibroblast cells, using direct light irradiation and treatment with the glucocorticoid Dexamethasone as references. tNMR significantly affected the cell autonomous clocks of unsynchronized mouse fibroblast cells NIH3-T3, but did not act as a Zeitgeber. Similar to light irradiation and in contrast to treatment with Dexamethasone, tNMR did not synchronize expression profiles of murine clock genes. However, irradiation with tNMR as well as light significantly altered mRNA and protein expression levels of Cryptochrome1, Cryptochrome2 and Clock1 for more than 24 h. Changes in mRNA and protein after different treatment durations, namely 6 and 12 h, appeared to be nonlinear. A nonlinear doseresponse relationship is known as hallmark of electromagnetic field induced effects on biological systems. The most prominent alterations were detected in murine HIF-1α protein, again in a nonlinear dose-response. In contrast to murine cells, zebrafish fibroblasts did not respond to tNMR at all. Light, a potent Zeitgeber for the peripheral clocks of fish, led to the expected synchronized clock gene oscillations of high amplitude, as did Dexamethasone. Hence, we conclude, mammalian peripheral clocks are more susceptible to tNMR than the direct light entrainable fish fibroblasts. Although light and tNMR did not act as Zeitgebers for the circadian clocks of unsynchronized murine cells, the significant observed effects might indicate downstream cellphysiological ramifications, which are worth future investigation. However, beside the effects tNMR exerts on the core clock mechanism of mammalian cells, the technology might be the first non-pharmacological approach to modify HIF-1α protein in cells and tissues. HIF-1α and the associated circadian clock play key roles in diseases with underlying ischemic background, such as infarct, stroke, and cancer and, also infectious diseases, such as Covid-19. Hence, low intensity magnet...

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“…[ 86 ] (2) The strong connection between the light‐sensing pathway and oxygen sensing pathway in the form of hypoxia and hypoxia‐inducible factor 1 (HIF‐1) signaling pathway. [ 87,88 ] Indeed, HIF‐1α can bind to the BMAL1 promoter; thus, directly regulating the molecular clock; in contrast, HIF‐1α promoter can be bound and controlled by CLOCK/BMAL1, thereby regulating hypoxia‐driven genes. [ 88 ] (3) The molecular clock not only has a strong influence on metabolic processes but it can act as a strong nutrient sensor [ 89,90 ] : this was clearly seen when a high fat diet in mice was able to alter circadian rhythm and molecular clock gene expression.…”

Section: Circadian Clock Machinery Acts As a Gatekeeper That Controlsmentioning

confidence: 99%

Why do cancer cells break from host circadian rhythm? Insights from unicellular organisms

Alamoudi

2021

BioEssays

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It is not clear why cancer cells choose to disrupt their circadian clock rhythms, and whether such disruption governs a selective fitness and a survival advantage. In this review, I focus on understanding the impacts of clock gene disruption on a simpler model, such as the unicellular cyanobacterium, in order to explain how cancer cells may alter the circadian rhythm to reprogram their metabolism based on their needs and status. It appears to be that the activation of the oxidative pentose phosphate pathway (OPPP) and production of NADPH, the preferred molecule for detoxification of reactive oxygen species, is a critical process for night survival in unicellular organisms. The circadian clock acts as a gatekeeper that controls how the organism will utilize its sugar, shifting sugar influx between glycolysis and OPPP. The circadian clock can thus act as a gatekeeper between an anabolic, proliferative mode and a homeostatic, survival mode.

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Circadian-Hypoxia Link and its Potential for Treatment of Cardiovascular Disease

Cited by 23 publications

References 210 publications

SMAD4 Overexpression in Patients with Sleep Apnoea May Be Associated with Cardiometabolic Comorbidities

SMAD4 Overexpression in Patients with Sleep Apnoea May Be Associated with Cardiometabolic Comorbidities

Therapeutic Nuclear Magnetic Resonance affects the core clock mechanism and associated Hypoxia-inducible factor-1

Why do cancer cells break from host circadian rhythm? Insights from unicellular organisms

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