Molecular clock REV-ERBα regulates cigarette smoke–induced pulmonary inflammation and epithelial-mesenchymal transition

Wang, Qixin; Sundar, Isaac K.; Lucas, Joseph H.; Muthumalage, Thivanka; Rahman, Irfan

doi:10.1172/jci.insight.145200

Cited by 42 publications

(54 citation statements)

References 55 publications

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“…The involvement of Rev-erbα in regulating cell functions has also been reported in other cell types. 11 , 43–45 Rev-erbα was shown to be a positive regulator that contributed to the amyloid plaque deposition in Alzheimer's disease by targeting microglial cells. 46 However, it functioned as a negative regulator in pulmonary inflammation 43 and neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

“… 11 , 43–45 Rev-erbα was shown to be a positive regulator that contributed to the amyloid plaque deposition in Alzheimer's disease by targeting microglial cells. 46 However, it functioned as a negative regulator in pulmonary inflammation 43 and neuroinflammation. 44 Thus, the role of Rev-erbα in regulating cell functions may depend on the cell types, and platelet-targeted Rev-erbα inhibition would be an optimal choice for clinical implications.…”

Section: Discussionmentioning

confidence: 99%

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Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation

Shi

Tong

Meng

et al. 2022

European Heart Journal

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Aims Adverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Circadian nuclear receptor Rev-erbα is an essential and negative component of the circadian clock. To date, the expression profile and biological function of Rev-erbα in platelets have never been reported. Methods and results Here, we report the presence and functions of circadian nuclear receptor Rev-erbα in human and mouse platelets. Both human and mouse platelet Rev-erbα showed a circadian rhythm that positively correlated with platelet aggregation. Global Rev-erbα knockout and platelet-specific Rev-erbα knockout mice exhibited defective in haemostasis as assessed by prolonged tail-bleeding times. Rev-erbα deletion also reduced ferric chloride-induced carotid arterial occlusive thrombosis, prevented collagen/epinephrine-induced pulmonary thromboembolism, and protected against microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. In vitro thrombus formation assessed by CD41-labelled platelet fluorescence intensity was significantly reduced in Rev-erbα knockout mouse blood. Platelets from Rev-erbα knockout mice exhibited impaired agonist-induced aggregation responses, integrin αIIbβ3 activation, and α-granule release. Consistently, pharmacological inhibition of Rev-erbα by specific antagonists decreased platelet activation markers in both mouse and human platelets. Mechanistically, mass spectrometry and co-immunoprecipitation analyses revealed that Rev-erbα potentiated platelet activation via oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway. Conclusion We provided the first evidence that circadian protein Rev-erbα is functionally expressed in platelets and potentiates platelet activation and thrombus formation. Rev-erbα may serve as a novel therapeutic target for managing thrombosis-based cardiovascular disease. Key question Adverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Whether circadian nuclear receptor Rev-erba is present in platelets and regulates platelet function remains unknown. Key finding We provide the first evidence that Rev-erba is functionally expressed in platelets and acts as a positive regulator of platelet activation/thrombus formation through the oligophrenin-1-mediated RhoA/ERM signalling pathway. Take home message Our observations highlight the importance of circadian clock machinery in platelet physiology and support the notion that Rev-erba may serve as a novel therapeutic target for managing thrombosis-based cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation

Shi

Tong

Meng

et al. 2022

European Heart Journal

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“…Another study from the same group showed the qRT-PCR analysis of chemokines and CCGs measured at two different time points or different ZT’s (every 4 h) analyzed from lung tissues or synchronized cells normalized with Rn18s as HKG 7 . We have previously used both Rn18s and Gapdh for acute and chronic circadian studies using environmental tobacco smoke exposures to determine gene expression of cytokines and CCGs in the lungs of WT and Rev-erbα KO mice 5 , 11 . Another report using hyperoxia model, evaluate the rhythmic expression of CCGs in WT mice (6 h interval) and pro-inflammatory genes (at ZT11 vs. ZT23) in the lungs of alveolar type II cell-specific Bmal1 KO was analyzed using Rn18s and 28S as HKG 8 .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of stable reference genes for qPCR normalization in circadian studies related to lung inflammation and injury in mouse model

Giri

Sundar

2022

Sci Rep

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Circadian rhythms have a profound effect on lung function and immune-inflammatory response in chronic airway diseases. Thus, understanding the molecular mechanisms of circadian gene expression of core clock-controlled genes (CCGs) may help better understand how it contributes to the physiology and pathology of lung diseases. Ongoing studies have been analyzing gene expression levels of CCGs in mouse lungs using quantitative real-time PCR (qRT-PCR). However, to date, there are no reports on the most stable reference gene in the mouse lung for circadian studies. Herein, we utilized an acute house dust mite (HDM)-sensitization mouse model to evaluate the stability of 10 reference genes commonly used for qRT-PCR normalization using 5 unique algorithms: GeNorm, NormFinder, BestKeeper, RefFinder and Qbase+. Rn18s was determined as the most stable reference gene across all samples evaluated, and Actb, the least stable reference gene. Furthermore, CircWave analysis showed no diurnal variation in the expression pattern for Rn18s but Actb showed strong diurnal changes in the lungs of both PBS (control) and HDM groups. We demonstrate systematically how using Actb as a housekeeping gene offsets the diurnal expression patterns of the CCGs and leads to statistically significant results which may not be the true reflection of the qRT-PCR analysis.

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“…REVERB agonists have been shown to protect against fibrosis in an animal model of lung fibrosis ( Cunningham et al, 2020 ). They are also protective with respect to the epithelial-to-mesenchymal transition ( Wang et al, 2021 ), as an inflammatory response, and reduce morbidity, and mortality in an animal model of smoke-induced lung damage ( Wang et al, 2021 ).…”

Section: Clock Genes As Targets For Lung Injurymentioning

confidence: 99%

The Role of Circadian Clock Genes in Critical Illness: The Potential Role of Translational Clock Gene Therapies for Targeting Inflammation, Mitochondrial Function, and Muscle Mass in Intensive Care

Ray

2022

J Biol Rhythms

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The Earth’s 24-h planetary rotation, with predictable light and heat cycles, has driven profound evolutionary adaptation, with prominent impacts on physiological mechanisms important for surviving critical illness. Pathways of interest include inflammation, mitochondrial function, energy metabolism, hypoxic signaling, apoptosis, and defenses against reactive oxygen species. Regulation of these by the cellular circadian clock (BMAL-1 and its network) has an important influence on pulmonary inflammation; ventilator-associated lung injury; septic shock; brain injury, including vasospasm; and overall mortality in both animals and humans. Whether it is cytokines, the inflammasome, or mitochondrial biogenesis, circadian medicine represents exciting opportunities for translational therapy in intensive care, which is currently lacking. Circadian medicine also represents a link to metabolic determinants of outcome, such as diabetes and cardiovascular disease. More than ever, we are appreciating the problem of circadian desynchrony in intensive care. This review explores the rationale and evidence for the importance of the circadian clock in surviving critical illness.

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Molecular clock REV-ERBα regulates cigarette smoke–induced pulmonary inflammation and epithelial-mesenchymal transition

Cited by 42 publications

References 55 publications

Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation

Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation

Evaluation of stable reference genes for qPCR normalization in circadian studies related to lung inflammation and injury in mouse model

The Role of Circadian Clock Genes in Critical Illness: The Potential Role of Translational Clock Gene Therapies for Targeting Inflammation, Mitochondrial Function, and Muscle Mass in Intensive Care

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