Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Gut microbiota-glycine-UCP3 axis modulates the protection of canagliflozin against cardiac hypertrophy

ABSTRACT: Canagliflozin (CANA), a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, exert cardioprotective effects and improve long-term clinical outcomes in heart failure patients without diabetes. However, given negligible myocardial SGLT2 expression, the mechanisms remain unclear. Here, we found that CANA altered the community structure of gut microbiota in mice subjected to pressure overload. Moreover, mice receiving microbiota transplants from TAC and CANA-treated mice exhibited better cardiac function compared to those receiving microbiota transplants from TAC-treated donors. Metabolite profiling identified glycine as a key mediator that protected against cardiac hypertrophy in mice. Importantly, the reduced glycine levels in hypertrophic mice were prevented by CANA treatment. We further demonstrated that Clostridium sp. was responsible for the degradation of glycine. Mechanistically, we showed that glycine activated the AMP-activated protein kinase α (AMPKα)/ peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) pathway, thus upregulating uncoupling protein 3 (UCP3) to preserve mitochondrial integrity and promote oxidative phosphorylation. UCP3 deficiency largely abolished the protective effect of CANA or glycine treatment against heart failure in mice. Our findings establish the gut microbiota-derived glycine/UCP3 signaling axis as a novel mechanism through which CANA exerts its anti-hypertrophic effects.

ORGANISM(S): Mus musculus

PROVIDER: GSE347125 | GEO | 2026/09/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Dapagliflozin protects against chronic heart failure in mice via inhibiting macrophage-mediated inflammation, independent of SGLT2 [RNA-Seq]

Project description:The specific mechanism of sodium-glucose cotransporter 2 (SGLT2) inhibitor in heart failure (HF) needs to be elucidated. In this study, we use SGLT2 global knockout (SGLT2-KO) mice to assess the mechanism of SGLT2 inhibitor on HF. Dapagliflozin ameliorates both myocardial infarction (MI)-and transverse aortic constriction (TAC) -induced HF. Global SGLT2-deficiency doesn’t exert protection against adverse remodeling in both MI- and TAC-induced HF models. Dapagliflozin blurs MI- and TAC-induced HF phenotypes in SGLT2-KO mice. Dapagliflozin causes major changes in cardiac fibrosis and inflammation. Based on single-cell RNA sequencing dapagliflozin causes significant differences in the gene expression profile of macrophages and fibroblasts. Moreover, dapagliflozin directly inhibites macrophage inflammation, thereby suppressing cardiac fibroblasts activation. The cardio-protection of dapagliflozin is blurred in mice treated with a C-C chemokine receptor type 2 (CCR2) antagonist. Taken together the protective effects of dapagliflozin against HF are independent of SGLT2, macrophage inhibition is the main target of dapagliflozin against HF.

2023-11-14 | GSE247062 | GEO

The effects of SGLT-2 inhibitors canagliflozin on hepatic transcription

Project description:We assessed the change in hepatic transciptional pattern after treatment with SGLT-2 inhibitors canagliflozin in a mice model of diet-induced obesity. Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 induces glycosuria and reduces glycemia. Given that SGLT2 inhibitors (SGLT2i) reduce mortality and CV risk in T2D, improved understanding of molecular mechanisms mediating these metabolic effects is required. Treatment of obese but nondiabetic mice with the SGLT2i canagliflozin (CANA) reduces adiposity, improves glucose tolerance despite reduced plasma insulin, increases plasma ketones, and improves plasma lipid profiles. We utilized an integrated transcriptomic-metabolomics approach to demonstrate that CANA modulates key nutrient-sensing pathways, with activation of AMPK and inhibition of mTOR, independent of insulin or glucagon sensitivity or signaling. Moreover, CANA induces transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce hepatic steatosis and diacylglycerol content, and increase hepatic and plasma levels of FGF21. Taken together, these data demonstrate that SGLT-2 inhibition triggers a fasting-like transcriptional and metabolic paradigm.

2020-04-16 | GSE148702 | GEO

Canagliflozin synergises with serine synthesis pathway inhibition mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia

Project description:T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy commonly driven by NOTCH1 activating mutations. A concomitant feature associated with NOTCH1 mutations is heightened oxidative metabolism enabling the exponential proliferation of T-ALL blasts. As such, targeting mitochondrial metabolism in T-ALL is an attractive therapeutic avenue. Canagliflozin (cana) is an FDA-approved sodium glucose co-transporter 2 inhibitor with known off-target effects on complex I and glutamate dehydrogenase. To date, the effects of cana on T-ALL are not known. Here, we show that cana possesses potent anti-leukaemic effects underpinned by proliferative defects, cell cycle disruption and apoptosis. These anti-leukaemic effects, driven by cana, are attributed to a perturbed tricarboxylic acid (TCA) cycle and mitochondrial metabolism and elevated mitochondrial ROS. Proteomic analysis revealed that cana treatment resulted in a compensatory increase in the expression of ATF4 targets, including upregulation of serine biosynthesis pathway and one-carbon metabolism enzymes. As such, restriction of serine and glycine synergized with cana treatment, further enhancing anti-leukaemic effects. Collectively, our study reveals cana creates a metabolic vulnerability that can be further exploited via dietary manipulation to treat T-ALL

2025-10-27 | PXD069587 | Pride

Gene expression profiles in the hearts of WT and Bcl-xL S14A KI mice after TAC or Sham

Project description:Acute increase of blood pressure by transverse aortic constriction (TAC), pressure overload, stimulates hypertrophic signaling in the heart, which is suppressed in Bcl-xL Ser14Ala knock-in mice.

2023-08-10 | GSE199705 | GEO

Transcription Factor Yin-Yang 1 governs cardiac metabolic reprogramming in response to exercise or pathological stress

Project description:The pleiotropic transcription factor Yin Yang 1 (YY1) regulates cellular metabolism in a stage- and tissue-dependent manner. However, its role in cardiac energetic regulation remains unclear. We found that cardiac-specific YY1 knockout (cYY1 KO) mice exhibited cardiac dysfunction after two weeks of swimming exercise, suggesting an impaired adaptive cardiac response. Further analysis revealed that exercise-induced upregulation of transcription factor networks controlling cardiac metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), was blunted in cYY1 KO mice. Consistently, citrate synthase activity, an indicator of mitochondrial content, was reduced in these mice. In response to transaortic constriction (TAC), cYY1 KO mice developed significantly exacerbated heart failure. RNA sequencing showed downregulation of metabolic genes and pathways, including PGC-1α, in TAC cYY1 KO mice hearts. Additionally, mitochondrial complex protein levels and complex I activity were reduced, consistent with suppressed metabolic gene transcription. Previously, we observed increased YY1 expression in hearts subjected to both exercise and TAC. However, while cardiac metabolism was enhanced with exercise, it was impaired with TAC. We found that p300 binding to YY1 increased during exercise, whereas histone deacetylase 3 (HDAC3) binding to YY1 increased in TAC hearts. These findings suggest that YY1-mediated transcriptional regulation of metabolic genes is modulated by the epigenetic regulators p300 and HDAC3.

2025-11-14 | GSE295777 | GEO

Glucose deprivation promotes lung adenocarcinoma de-differentiation due to unbalanced EZH2 activity

Project description:Lung cancer is the most frequent cancer-related cause of death, and adenocarcinoma (LUAD) is the most frequent type. Despite the recent success of immunotherapies, survival of lung cancer patients has not significantly improved in the last decades. New therapies are necessary. We have previously identified sodium-glucose transporter 2 (SGLT2) as the major responsible for glucose uptake in LUAD, and we have showed that treatment with SGLT2 inhibitors significantly delays LUAD development and prolongs survival in murine models. However, our data shows that SGLT2 inhibitors also induce de-differentiation of LUAD cells, leading to a more aggressive phenotype and increased resistance to cisplatin. Glucose deprivation causes reduced αKG levels, leading to reduced activity of αKG-dependent histone demethylases and consequent histone hypermethylation. Supplementation of αKG or inhibition of the histone methyltransferase EZH2 reverse this phenotype, suggesting that this de-differentiated phenotype depends on insufficiency of αKG-dependent histone demethylases and unbalanced EZH2 activity. Consistently, double treatment with an SGLT2 inhibitor and an EZH2 inhibitor significantly reduces the tumor burden in a genetically engineered murine model of LUAD. We further characterized the effect of low glucose-induced tumor de-differentiation, identifying stabilization of hypoxia inducible factor 1α (HIF1α) as a major pathway responsible for the acquisition of a more aggressive phenotype following glucose deprivation. Finally, we identified an HIF1α-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further our knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to nutrient deprivation and identifying novel targets to prevent the development of resistance to metabolic therapies.

2022-12-31 | E-MTAB-11253 | biostudies-arrayexpress

Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity [Autoimmune Profiling]

Project description:Augmented T-cell function leading to host damage in autoimmunity is supported by metabolic dysregulation. Targeting immunometabolism for the treatment of autoimmunity by repurposing clinically approved metabolic modulators, such as those used to treat people with type 2 diabetes (T2D), is therefore an attractive avenue. Canagliflozin, a class of the newest type of T2D drug – sodium glucose co-transporter 2 (SGLT2) inhibitors – has known off-target effects including mitochondrial glutamate dehydrogenase (GDH) and complex I inhibition. To date, the effects of SGLT2 inhibitors on human T-cell function are extremely limited. Here, we analysed 784 genes using the Nanostring nCounter® Autoimmune Profiling Panel and discovered 42 genes that were differentially regulated between canagliflozin-treated (cana, C; n = 6) and DMSO vehicle control (V; n = 6) T-cells. Of these genes, 39 were downregulated, including IL2, CSF2 and CCL20; whilst 3 were upregulated, including SELL. Dapagliflozin was used as another control, as this SGLT2 inhibitor does not exhibit any known off-target effects like canagliflozin. Here, there were no differentially expressed genes between dapagliflozin-treated (dapa, D; n = 4) and DMSO vehicle control (V; n = 4) T-cells. These analyses allowed a greater understanding of the global changes in T-cell function that occur in response to treatment with SGLT2 inhibitors.

2023-04-04 | GSE228909 | GEO

Project description:16S rRNA analysis of the effects of CANA on gut microbiota in TAC-induced cardiac hypertrophy in mice

| PRJNA1528795 | ENA

Microarray analysis of heart gene expression in wild type and JMJD2A heart specific transgenic mice after sham and thoracic aortic constriction surgery

Project description:Cardiac hypertrophy and failure are accompanied by a reprogramming of gene expression that involves transcription factors and chromatin remodeling enzymes. Little is known about the role of histone methylation and demethylation in this process. To understand the role of JMJD2A, a trimethyl demethylase for histone 3 lysine 9 and 36, in cardiac hypertrophy, we generated heart specific JMJD2A deletion (JMJD2A hKO) and overexpression (JMJD2A-Tg) mouse lines. JMJD2A hKO and JMJD2A-Tg mice are viable and have no overt baseline phenotype. However, they have altered responses to cardiac stresses. While inactivation of JMJD2A in hKO mice resulted in an attenuated hypertrophic response to transverse aortic constriction (TAC)-induced pressure overload compared to that of control littermates, JMJD2A-Tg mice have exacerbated cardiac hypertrophy after TAC. We identified four-and-a-half LIM domains 1 (FHL1) as a novel target of JMJD2A. JMJD2A binds to the FHL1 promoter in response to TAC and upregulates the expression of FHL1. Binding of JMJD2A to the FHL1 promoter is associated with downregulation of trimethylated H3K9. Upregulation of FHL1 by JMJD2A is mediated through SRF and myocardin, and requires its demethylase activity. The expression of JMJD2A is upregulated in human hypertrophic cardiomyopathy patients. Our studies reveal that JMJD2A promotes cardiac hypertrophy by synergistically upregulating SRF/myocardin-targeted genes and suggest a novel mechanism of reprogramming of gene expression involved in cardiac hypertrophy. Six to eight years old wildtype and JMJD2A heart specific transgnic mice were undergone either sham or TAC surgery. After 3 weeks, mice were sarcirificed to harvest heart. RNA was extracted from heart samples and treated with DNase, followed by biotin-labeling and microarray hybridization.

2011-06-02 | E-GEOD-27689 | biostudies-arrayexpress

The effect of mitochondrial uncoupling in murine skin samples using Keratin 5-UCP3 trangenic model

Project description:Uncoupling protein 3 (UCP3) is a nuclear encoded, member of the mitochondrial solute carrier family which localizes to the inner mitochondrial membrane and dissipates the proton gradient used to drive ATP synthesis. UCP3 is expressed at low levels in skin and our lab has demonstrated that overexpression of UCP3 in epidermis (K5-UCP3 mice) provides marked resistance to two-stage chemical carcinogenesis protocols in skin. To further understand the mechanisms by which UCP3 promotes this cancer resistant phenotype, we performed a microarray analysis of dorsal skin biopsies from wild type FVB/N and K5-UCP3 mice. The results of this array indicate that UCP3 overexpression in skin enhances keratinocytes differentiation and fatty acid oxidation in skin, and taken together with other data we have provided a mechanistic link between fatty acid oxidation and Akt inhibition in UCP3-mediated cancer resistance.

2015-07-18 | GSE71038 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data