Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Abnormal circadian rhythms exacerbate dilated cardiomyopathy by reducing the ventricular mechanical strength

ABSTRACT: Dilated cardiomyopathy (DCM) has etiological and pathophysiological heterogeneity. Abnormal circadian rhythm (ACR) is related to the development of DCM in animal models, but exploration based on clinical samples is lacking. Sleep apnea (SA) is the most common disease related to ACR, and we chose SA as the study object to explore ACR-DCM. We included a DCM cohort and divided it into SA (n=76) and without SA group (n=29). RT-qPCR was used to determine the change of rhythm gene expression pattern. We used single-nucleus RNA sequencing (snRNA-seq) to explore the abnormal transcriptional patterns in the ACR group, and we verified the findings by pathological staining, atomic force microscopy (AFM), and Rev-erbα/β knockout (KO) mice analysis. DCM patients with SA showed decreased amplitude of rhythm gene expression. SA group showed more severe dilation of left heart chambers. From snRNA-seq, ACR-DCM lost the morning transcriptional patterns, detailly, actin cytoskeleton organization of cardiomyocytes (CMs) disrupted and hypertrophy aggravated, and the proportion of activated fibroblasts (Fibs) decreased with the reduction of fibrotic area ratio. The results of pathological staining, mechanical experiments, and transcriptional feature of Rev-erbα/β KO mice supported the above findings. The severe dilation of the left ventricular (LV) wall in DCM patients with SA was associated with a decrease in structural strength, and phenotypic changes of CMs and Fibs were involved in this process. ACR-DCM was histopathologically characterized by a fluffy ventricular wall.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270258 | GEO | 2024/07/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [ChIP_seq]

Project description:The circadian clock acts at the genomic level to coordinate internal behavioral and physiologic rhythms via the CLOCK-BMAL transcriptional heterodimer. Although the nuclear receptors REV-ERBα and β have been proposed to contribute to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential we generated comparative cistromes of both Rev-erb isoforms, which revealed shared recognition at over ~50% of their total sites and extensive overlap with the master clock regulator Bmal. While Rev-erbα has been shown to directly regulate Bmal expression, the cistromic analysis reveals a more profound connection between Bmal and Rev-erbα and β regulatory circuits than previously suspected. Genes within the intersection of the Bmal and Rev-erb cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erbα/β function by creating double-knockout mice (DKOs) profoundly disrupted circadian expression of core clock and lipid homeostatic genes. As a result, DKOs show strikingly altered circadian wheel-running behavior and deregulated lipid metabolism. These data reveal an integral role of Rev-erbα/β in clock function as well as provide a cistromic basis for the integration of circadian rhythm and metabolism. Identification of Reverb alpha and Reverb beta binding sites in mouse liver at ZT8

2012-03-28 | E-GEOD-34019 | biostudies-arrayexpress

Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [ChIP_seq]

2012-03-29 | GSE34019 | GEO

Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [Expression array]

2012-03-29 | GSE34018 | GEO

Myocardial Rev-erb regulates metabolic diurnal rhythm in heart failure

Project description:Rev-erbα/β are druggable components of the molecular circadian clock. Rev-erb agonists can mitigate pressure overload-induced cardiac hypertrophy and myocardial infarction in mice, while Rev-erb antagonist increases myocardial ischemia-reperfusion tolerance ex vivo at the sleep-to-wake transitionHow cardiac Rev-erb regulates heart function has not been studied in vivo. ChIP-seq of Rev-erbα in the heart confirmed the robust diurnal rhythmicity of Rev-erbα genome binding with about 5 times more binding at ZT9 than at ZT21.

2021-12-08 | GSE153150 | GEO

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα on tau pathology are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolic processes, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

2023-07-12 | GSE236875 | GEO

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα deletion in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deficient enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

2023-08-09 | PXD043877 | Pride

Secretome from human placenta–derived mesenchymal stem cells rescues ovarian function and circadian rhythm in mice with cyclophosphamide-induced primary ovarian insufficiency

Project description:Primary ovarian insufficiency (POI) is an early decline in ovarian function that leads to infertility. Conventional treatments for chemotherapy-induced POI are unsatisfactory. Mesenchymal stem cells (MSCs) have emerged as a therapeutic option, but the impact of estrogen niche-respond MSC secretome on ovarian regeneration and circadian rhythm remains unknown. This study revealed that the secretome of ER+pcMSCs (conditioned medium [CM] and E2-CM, respectively) significantly reduced the CTX-induced defects in ovarian folliculogenesis and circadian rhythm. The CM/E2-CM also reduced granulosa cell apoptosis and rescued angiogenesis in POI ovarian tissues. E2-CM presented a better effect than the CM. Cytokine array analysis showed a significant increase in cytokine/growth factors associated with immunomodulation and angiogenesis (including angiogenin). Neutralizing angiogenin in the CM/E2-CM significantly decreased its ability to promote HUVEC tube formation in vitro. Importantly, the ER+pcMSC secretome restored the CTX-induced circadian rhythm defects, including the expression of both the genes and proteins associated with ovarian circadian clock (such as Rora, E4bp4, Rev-erbα, and Dbp) and the locomotor activity. Further exosomal miRNA analysis showed the involved miRNAs in targeting the genes associated with POI rescue (Pten and Pdcd4), Caspase-3, estrogen synthesis (Cyp19a1), and importantly the ovarian clock regulation (E4bp4, Rev-erbα and Rev-erbβ).

2024-10-23 | GSE247568 | GEO

Timed use of digoxin prevents heart ischemia-reperfusion injury through a REV-ERBα-UPS signaling pathway

Project description:Myocardial ischemia-reperfusion injury (MIRI) is a major threat to heart functional integrity and pharmacological means to achieve cardioprotection are sorely needed. The sequential hypoxic/normoxic status of the cardiac tissue triggers life-threatening damages through the activation of multiple intra-cellular pathways. Heart tolerance to MIRI varies according to a day-night cycle and is regulated by components of the molecular clock such as the transcriptional repressor and nuclear receptor REV-ERBα. Timed REV-ERBα antagonism alleviates sensitivity to myocardial infarction in mice. Here we show that timed administration of digoxin is cardioprotective by triggering REV-ERBα protein degradation. Kinomics and transcriptomic assays revealed that in several cardiomyocyte cellular models, digoxin and other cardiotonic steroids induced multiple signaling pathways. Pharmacological inhibition and knockdown approaches revealed that inhibition of the Src tyrosine-kinase partially alleviated digoxin-induced REV-ERBα degradation, which was fully prevented upon proteasome inhibition. REV-ERBα is increasingly ubiquitinylated in digoxin-treated cells, and its degradation depends on its ability to bind its natural ligand, heme. In unchallenged conditions, the proteasomal degradation of REV-ERBα is controlled by several known (HUWE1, FXW7, SIAH2) or novel (CBL, UBE4B)E3 ubiquitin ligases. Only SIAH2 together with the proteasome subunit PSMB5 were found tocontribute to the digoxin-induced degradation of REV-ERBα. Taken together, these results show that controlling REV-ERBα proteostasis is an appealing cardioprotective strategy, and bring further support to the rationale, timed use of CTS in prophylactic cardiac preconditioning to MIRI.

2022-09-13 | PXD036607 | Pride

Myocardial Rev-erb-mediated diurnal metabolic rhythm( Part1/3)

Project description:Agonists and antagonists of nuclear receptor Rev-erbα/β, key components of the circadian clock, can benefit the heart. Here, we show that mice with cardiomyocyte-specific knockout (KO) of Rev-erbα/β display progressive cardiac dilation and lethal heart failure. Inducible ablation of Rev-erbα/β in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, particularly in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, particularly in the dark cycle. These findings delineate temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism.

2021-09-10 | ST001915 | MetabolomicsWorkbench

Myocardial Rev-erb-mediated diurnal metabolic rhythm (Part 2/3)

2021-09-10 | ST001916 | MetabolomicsWorkbench