Transcriptomic study of heart tissue from diabetic cardiomyopathy mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE161931 | GEO | 2021/09/24
REPOSITORIES: GEO
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Project description:Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intra-cardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalizes components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalizes insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescues cardiac lusitropy, improves exercise intolerance, and ameliorates hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy, and also improve systemic glycemic control.
2023-10-24 | PXD044236 | Pride
Project description:Diabetic cardiomyopathy (DbCM) occurs independently of cardiovascular diseases or hypertension, often leading to heart failure and death. To elucidate the molecular mechanisms involved in the DbCM progress, we performed quantitative proteomic profiling analysis in the left ventricle (LV) of leptin receptor‐deficient mice. Six‐month‐old C57BL/6Jlepr/ lepr (db/db) mice exhibited a phenotype of DbCM. By quantitative shotgun proteomic analysis, we identified 53 differentially expressed proteins in db/db mice, mainly associated with energy metabolism. The subunits of ATP synthase that form the F1 domain and Cytochrome c1, a catalytic core subunit of the complex III that is responsible for electron transfer to Cytochrome c, were upregulated in diabetic LVs. Upregulation of these key proteins may represent an adaptive mechanism by the diabetic heart resulting in increased electron transfer and thereby enhancement of mitochondrial ATP production. Conversely, diabetic LVs also showed a decrease in peptide levels of NADH dehydrogenase 1 beta subcomplex subunit 11, a subunit of complex I that catalyzes the transfer of electrons to ubiquinone. Moreover, an atypical kinase COQ8A, an essential lipid‐soluble electron transporter involved in the biosynthesis of ubiquinone, was also downregulated in diabetic LVs. Our study indicates that despite attempts by hearts from the diabetic mice to augment mitochondrial ATP production, decreased levels of key components of the electron transport chain may contribute to impaired mitochondrial ATP production.
2021-12-02 | PXD029566 | Pride
Project description:Diabetic cardiomyopathy (DCM) is one of the most serious complications of diabetes. Recent cardiology studies suggest that spermine has cardioprotective effect. Here, we used proteomics analyses to reveal the underlying research target in type 2 diabetic mouse model treated with spermine. Left ventricular tissue was excised from 9 mice (Control group, 3; T2D group（db/db mouse）, 3; T2D+SP group, 3) and analyzed. Quantitative analysis of the global proteome were detected using 4D label-free technique,and differentially expressed proteins (DEPs) were used to perform bioinformatic analyses.
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Project description:Diabetes is associated with altered metabolism, but how altered metabolism contributes to the development of complications such as diabetic kidney disease is unknown. We used a systems approach with transcriptomics and mass spectrometry (MS)-based metabolomics to determine alterations in carbohydrate and lipid metabolism in kidney cortex tissue from 24-week-old BKS db/db diabetic mice and db/+ controls. Glomerular-deprived kidney cortex (kidney proximal tubule) gene expression was profiled and compared with metabolite data. Transcriptomic and metabolomic profiling demonstrated an increase in both glycolysis and fatty acid beta-oxidation,
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Project description:The majority of diabetics are susceptible to cardiac dysfunction and heart failure, while conventional drug therapy cannot correct diabetic cardiomyopathy (DCM) progression. Herein, we assessed the potential role and therapeutic value of ubiquitin-specific protease 28 (USP28) on the metabolic vulnerability of DCM. PPARα-/- in the db/db background mice were constructed to check the mechanism of USP28 in vivo. Inducible cardiac-specific deletion of Mfn2 in the db/db background mice was utilized to evaluate USP28-mediated cardioprotection. chromatin immunoprecipitation (ChIP) assays revealed that PPARα promote mitofusin 2 (Mfn2) transcription, thereby impeding mitochondrial morphofunctional defects.
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Project description:Fenofibrate lowers cardiac lipid accumulation and attenuates diabetic cardiomyopathy in db/db mice.
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Project description:To explore the unique pathogenesis of DCM and analyzed the differences in gene expression, associated pathways and immune cell infiltration among different organs that are targeted by high glucose by bioinformatics-based strategy. In order to find the specific factors that trigger DCM, we contrasted the gene profile of DCM to that of other diabetic diseases including diabetic peripheral neuropathy (DPN) and nephropathy (DN). we performed RNA-seq and miRNA sequencing on heart tissue from db/db mice to explore the transcriptome alterations in DCM pathogenesis including lncRNA, miRNA and mRNA.
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Project description:To explore the unique pathogenesis of DCM and analyzed the differences in gene expression, associated pathways and immune cell infiltration among different organs that are targeted by high glucose by bioinformatics-based strategy. In order to find the specific factors that trigger DCM, we contrasted the gene profile of DCM to that of other diabetic diseases including diabetic peripheral neuropathy (DPN) and nephropathy (DN). we performed RNA-seq and miRNA sequencing on heart tissue from db/db mice to explore the transcriptome alterations in DCM pathogenesis including lncRNA, miRNA and mRNA.
2023-05-10 | GSE211107 | GEO
Project description:Major causes of lipid accumulation in liver are increased import, synthesis or decreased catabolism of fatty acids. The latter is caused by dysfunction of cellular organelle controlling energy homeostasis, i.e. mitochondria. However, peroxisomes appear to be an important organelle in lipid metabolism of hepatocytes, but little is known about their role in the development of non-alcoholic fatty liver disease (NAFLD). To investigate the role of peroxisomes next to mitochondria in excessive hepatic lipid accumulation we used the leptin resistant db/db mice on C57BLKS background, a mouse model that develops hyperphagia induced diabetes with obesity and NAFLD. We used microarrays to determine differences in hepatic gene expression in a mouse model for NAFDL (BKS.Cg-Leprdb (db/db)) and their wildtype littermates C57BL/KSlepr+/+ (BKS) to determine the effect of persistent hepatic lipid accumulation.
2015-03-23 | GSE59930 | GEO
Project description:A better understanding of the molecular mechanisms underlying the development and progression of diabetic neuropathy (DN) is essential for the design of mechanism-based therapies. We examined changes in global gene expression to define pathways regulated by diabetes in peripheral nerve. Microarray data for 24 week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes (DEGs); DEGs were further used for functional enrichment analysis and network analysis to identify biological processes and pathways differentially regulated in the db/db nerve. Expression profile clustering was performed to identify co-expressed DEGs. A set of co-expressed lipid metabolism genes was used for promoter sequence analysis.We identified 4,017 DEGs; 2,122 genes were up-regulated and 1,895 genes were down-regulated in the db/db relative to the db+ samples. Over-represented biological processes identified by the functional enrichment analysis include cell cycle, lipid metabolic process, lipid transport, carbohydrate metabolic process, response to stress, apoptosis, axonogenesis and cell adhesion. Pathways regulated in the db/db nerve include lipid metabolism, carbohydrate metabolism, energy metabolism, PPAR signaling, apoptosis, and axon guidance. The majority of DEGs in the glycolysis, TCA cycle, oxidative phosphorylation, fatty acid metabolism, glycerolipid metabolism, mitochondrial fatty acid elongation, lipid transport, adipocytokine signaling, PPAR signaling, and apoptosis pathways are up-regulated, whereas most of the axonogenesis-related genes are down-regulated in db/db nerve. A network of DEGs based on their co-citation in literature identified regulatory relationship between Tnf-α and key genes from the regulated pathways. Promoter sequence analysis identified over-represented transcription factor binding site (TFBS) motifs in the promoter regions of twenty two co-expressed lipid metabolism-related genes suggesting coordinated regulation of these genes by multiple transcription factors (TF). Furthermore, TF binding to these TFBS and differentially regulated in our data are annotated with nervous system development and immune response suggesting possible co-regulation of lipid metabolism, nervous system development and stress response genes. Gene expression changes in our data are consistent with pathological characteristics observed in DN including axon degeneration and demyelination, and support existing hypotheses regarding hyperglycemia mediated nerve damage in DN. Our findings support the role of hyperglycemia-induced oxidative stress and ischemia in nerve injury. Our results also support the hypothesis of oxidized lipid-mediated nerve injury and increased mitochondrial oxidative stress in dyslipidemia. Moreover, our analyses revealed a possible co-regulation mechanism connecting hyperlipidemia, stress response and axonal degeneration. Microarray data for 24 week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes
2011-02-18 | E-GEOD-27382 | biostudies-arrayexpress