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Gene profiling of heart atria in PI3K and Mst1 mouse models

ABSTRACT: We used microarrays to detail genome-wide gene expression underlying cardiac myocyte pathologies and identified candidate genes and specific pathways affecting cardiac myopathies Keywords: transgenics, cardiac disease analysis Mouse heart atria were dissected for RNA extraction and hybridisation on Affymetrix microarrays. We sought to profile gene expression from the transgenic mouse models for non-transgenics (Ntg), dnPI3K (dominant negative for phosphoinositide 3-kinase), Mst1 (mammalian sterile 20-like kinase 1) and dnPI3K-Mst1 (double mutant) mouse models with a combined background of C57BL/6/FVB/N inbred strains. Pathological insults on cardiac myocytes are investigated

ORGANISM(S): Mus musculus

SUBMITTER: RubyCY Lin

PROVIDER: E-GEOD-12420 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation.

Pretorius Lynette L Du Xiao-Jun XJ Woodcock Elizabeth A EA Kiriazis Helen H Lin Ruby C Y RC Marasco Silvana S Medcalf Robert L RL Ming Ziqiu Z Head Geoffrey A GA Tan Joon Win JW Cemerlang Nelly N Sadoshima Junichi J Shioi Tetsuo T Izumo Seigo S Lukoshkova Elena V EV Dart Anthony M AM Jennings Garry L GL McMullen Julie R JR

The American journal of pathology 20090813 3

Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110alpha) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that ...[more]

PMID: 19679877

Similar Datasets

Gene profiling of heart atria in PI3K and Mst1 mouse models

Project description:We used microarrays to detail genome-wide gene expression underlying cardiac myocyte pathologies and identified candidate genes and specific pathways affecting cardiac myopathies Keywords: transgenics, cardiac disease analysis

2009-07-25 | GSE12420 | GEO

Human embryonic stem cells differentiated in dopaminergic neurons

Project description:Human embryonic stem cells have been a great interest due to its potential to provide a renewable source of surrogate dopamine neurons for transplantation into ParkinsonM-bM-^@M-^Ys disease patients. We have differentiated hESCs with a monolayer of PA6 cells under 2D and 3D systems for 28 days. Genome-wide microarray analysis showed that our 3D samples increased expression of genes that are involved in neuronal developments such as Wnt, hedgehog and mitogen-activated protein kinase (MAPK) signalling pathways. The results suggest that the 3D differentiation system may have affected the regulatory or signalling mechanisms which enhanced the rate of differentiation towards ectoderm. 3 biological replicates for 2D samples and 2 biological replicates for 3D samples.

2013-01-03 | E-GEOD-43235 | biostudies-arrayexpress

Leukotriene B4 receptor 1 antagonist in combination with kinase MST1/2 inhibitor has potential for treatment of myocardial infarction

Project description:Timely inhibition of inflammation and initiation of resolution are important for the repair of injured tissues. Pharmacological inhibition of mammalian STE20-like protein kinase 1/2 (MST1/2) with XMU-MP-1 might augment tissue regeneration and repair by suppressing apoptosis and increasing cell proliferation. However, MST1 has anti-inflammatory activity, inhibition of which may result in therapy failure. Here, we identified an approach with the potential to overcome this limitation by protecting against cardiac inflammation resulting from inhibition of MST1 in macrophages. We found exacerbation of cardiac dysfunction in LysMCre-mediated Mst1/2-deficient mice after myocardial infarction (MI). This effect was attributed to a shift of macrophage subtypes from those expressing Cxcl2 and Cd163 toward those with Ccl2 and Ccl4 expression. Mass spectrometry identified leukotriene B4 (LTB4) as the lipid mediator that was upregulated in the absence of MST1. We found that MST1 phosphorylated 5-lipoxygenase (5-LOX) at its T218 residue, disrupting the interaction between 5-LOX and 5-LOX-activating protein, and resulting in reduction of LTB4 production. By contrast, a 5-LOXT218A variant showed no response to MST1. Moreover, treatment of peritoneal macrophages with LTB4 or with medium conditioned by Mst1-deficient macrophages resulted in high Ccl2 and Ccl4 expression and low Cxcl2 and Cd163 expression, except when the cells were co-treated with the LTB4 receptor 1 (BLT1) antagonist CP105696. Furthermore, CP105696 ameliorated cardiac dysfunction in LysMCre-mediated Mst1/2-deficient mice and enhanced cardiac repair in wild-type mice treated with XMU-MP-1 after MI. The combination of an MST1/2 inhibitor and a BLT1 antagonist represents a promising strategy for combatting the effects of MI.

2021-12-13 | GSE181935 | GEO

Human induced pluripotent stem cells derived from a sporadic Alzheimer's disease patient

Project description:Induced pluripotent stem cell (iPSC) disease models have been generated for a number of diseases, and some have shown their potential utilization for pathological and drug toxicological evaluations. We have generated two hiPSC clones from a non-familial Alzheimerâs patient (AD-iPSCs), which expressed typical undifferentiated markers and fulfilled standard pluripotency assays. Genome-wide microarray analysis revealed that AD-iPSCs are highly similar to control hiPSCs and hESCs, albeit with some noticeable differences in several genes: DNAJC15, GRPR, NAIP and SNORD116-18. Several other biomarkers were differentially expressed in AD-iPSC clones, which were implicated in memory impairment and AD. Furthermore, well characterized familial AD-associated genes (APP, PSEN1, PSEN2) and non-familial (A2M, APOE, GAP43, MAOA, MPO, PLAT, PLAU, SORL1, SNCA) exhibited different expression patterns but were largely reset upon reprogramming into a pluripotent state. Overall, hiPSCs can be good candidates for AD modeling and may represent an in vitro alternative to studying disease mechanisms and drug discovery/toxicology studies. Fibroblasts and two hiPSC clones from a non-familial Alzheimerâs patient (AD-iPSCs) were analyzed. For each cell sample, 2-3 biological replicates were obtained.

2015-12-31 | E-GEOD-31163 | biostudies-arrayexpress

Profiling oxidative stress in Saccharomyces cerevisiae by oxidation of transcription factor Swi6p

Project description:Cell cycle sensing of oxidative stress in Saccharomyces cerevisiae by oxidation of a specific cysteine residue in the transcription factor Swi6p. Yeast cells begin to bud and enter S phase when growth conditions are favourable during G1 phase. When subjected to oxidative stress, cells arrest at G1 delaying entry into the cell cycle allowing repair of cellular damage. Hence, oxidative stress sensing is coordinated with the regulation of cell cycle. We identified a redox sensing cysteine residue in the cell-cycle regulator of Saccharomyces cerevisiae, Swi6p, at position 404. Mutation of Cys404 to alanine abolished the ability of the cells to arrest at G1 upon treatment by lipid hydroperoxide. By constructing a truncated form of Swi6p, the Cys404 residue was found to be oxidised when cells were subjected to the oxidant. Furthermore, microarray analysis revealed that mutation of Cys404 to alanine led to loss of suppression of G1-cyclins CLN1 and PCL1 when the cells were exposed to lipid hydroperoxide. In conclusion, oxidation of Cys404 serves as a molecular sensor of oxidative stress and inhibits entry into the cell cycle by suppression of G1-cyclin expression. We used a gene expression approach to assess the involvement of Cys404 in oxidative stress by mutating this residue to alanine in order to study whether it contributes to Swi6p, a transcriptional factor, function for redox regulation of the cell cycle. Wild type, swi6-deletant, and swi6 C404A-mutated yeast cells were treated with either linoleic acid hydroperoxide (LoaOOH) or control. Three replicates per group/treatment.

2011-01-31 | E-GEOD-18334 | biostudies-arrayexpress

Human iPSCs derived under feeder free conditions displays an unqiue cell cycle and DNA replication genotype

Project description:Induced pluripotent stem cells (iPSCs) have been generated from various somatic cells under feeder-layer conditions. These feeder-derived iPSCs generated in different labs exhibit greater variability than between different traditional embryo derived hESC lines. For that reason, it is important to develop a standard and defined system for deriving autologous patient stem cells. We have generated iPSCs under feeder-free conditions using Matrigel coated vessels in chemically defined medium, mTeSR1. These feeder-free derived iPSCs are in many ways similar to feeder-derived iPSCs and also to hESCs, with respect to their pluripotent gene expression (OCT4, NANOG, SOX2), protein expression (OCT4, NANOG, SSEA4, TRA160) and differentiation capabilities. We conducted a whole genomic transcript analysis using Affymetrix Human Gene 1.0 ST arrays to elucidate the important differences between traditional feeder-derived iPSCs and feeder-free derived iPSCs. We reveal that feeder-free iPSCs have over-represented terms belonging to DNA replication and cell cycle genes which are lacking in feeder-derived iPSCs. Feeder-free iPSCs are in many aspects more similar to hESCs including; apoptosis, chromatin modification enzymes and mitochondrial energy metabolism. We have also identified potential biomarkers for fully reprogrammed iPSCs (FRZB) and partially reprogrammed iPSCs (POTEG, MX2) based on their expression trends across all cell types. In conclusion, feeder-free derived iPSCs is transcriptomically more similar to hESCs than feeder derived iPSCs, in many biological functions. For each cell sample, 2 or 3 biological replicates were obtained.

2011-06-03 | E-GEOD-21655 | biostudies-arrayexpress

The Hippo kinase MST1 negatively regulates the differentiation of follicular helper T cells

Project description:In order to explore the regulatory mechanism of MST1 kinase on Tfh differentiation and function, we sorted Tfh cells in the spleen of WT and Mst1 KO mice 8 days after intraperitoneal sensitization, and extracted total RNA from the collected cells as samples for sequencing analysis.

2022-08-23 | GSE211808 | GEO

Microarray of Mst1/2 deleted epithelial cells from E18.5 mouse lungs

Project description:ShhCre;Mst1/2flx/flx (Mst1/2 D/D) mice were generated to conditionally delete Mst1 and Mst2 from epithelial progenitors during lung morphogenesis. Lungs from E18.5 control and Mst1/2 D/D mice were mechanically and enzymatically dissociated to generate single cell suspension. Epcam(+) cells were isolated using magnetic microbeads. Microarray analysis of mRNAs isolated from Epcam(+) epithelial cells from E18.5 control and Mst1/2 D/D mice was performed to identify transcriptional changes following deletion of the mammalian Hippo kinases (Mst1 and Mst2) from the embryonic lung. The mammalian Hippo kinases, Mst1 and Mst2, were conditionally deleted in epithelial progenitors of the developing lung using ShhCre. Epcam(+) epithelial cells were isolated from the lungs of E18.5 control and Mst1/2 deleted mice. mRNA isolated from Epcam(+) epithelial cells was analyzed by microarray.

2015-01-01 | E-GEOD-61582 | biostudies-arrayexpress

RNA-seq analysis of Mst1/2 deleted bronchiolar epithelial cells from adult mouse lungs

Project description:Mst1 and Mst2 were conditionally deleted from non-ciliated bronchiolar epithelial cells in the mature lung. Bronchiolar epithelial cells from control and Mst1/2 deleted mice were isolated by cell sorting and used for RNA-seq analysis. Scgb1a1-rtTA/tetO-Cre/Mst1;2-flx/flx (Mst1/2 D/D) mice were generated to conditionally delete Mst1 and Mst2 from non-ciliated, secretory bronchiolar epithelial cells. Adult mice were maintained on doxycycline food for 16 days to induce deletion of Mst1/2. Lin-/CD326+/CD24-intermediate cells were isolated by fluorescence cell sorting to enrich for the targeted airway epithelial cells. mRNA isolated from Lin-/CD326+/CD24-intermediate cells from control and Mst1/2 D/D mice was pooled and analyzed by RNA-seq to identify transcriptional changes following deletion of Mst1 and Mst2 from mature lung bronchiolar epithelial cells.

2015-01-01 | E-GEOD-61627 | biostudies-arrayexpress

Hippo kinases Mst1 and Mst2 sense and amplify IL-2R−STAT5 signaling in Treg cells to establish stable regulatory activity

Project description:Interleukin-2 (IL-2) and downstream transcription factor STAT5 are important for maintaining regulatory T (Treg) cell homeostasis and function. Tregs can respond to low levels of IL-2, but the mechanisms by which STAT5 is activated during partial IL-2 deficiency remain uncertain. We identified the serine-threonine kinase Mst1 as a signal-dependent amplifier of IL-2−STAT5 activity in Tregs. Tregs had high Mst1 and Mst2 (Mst1−Mst2) activity that was crucial to prevent tumor resistance and autoimmunity. Mechanistically, Mst1−Mst2 sensed IL-2 signals to promote the STAT5 activation necessary for Treg cell homeostasis and lineage stability, and maintain the highly suppressive phophorylated-STAT5+ Treg cell subpopulation. Unbiased quantitative proteomics revealed an association of Mst1 with the cytoskeletal DOCK8−LRCHs module that shaped activity Rho-family GTPase Rac activity, which in turn mediated STAT5 activation in Tregs. Collectively, IL-2−STAT5 signaling critically depends upon Mst1−Mst2 functions to maintain a stable Treg cell pool and immune tolerance. We used microarrays to compare the global transcription profiles of WT and Mst1/Mst2-null Treg cell populations

2018-11-08 | GSE120711 | GEO

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