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Global gene expression profiles of MT knockout and wild-type mice in the condition of doxorubicin-induced cardiomyopathy

ABSTRACT: The present study was designed using MT knockout mice in concert with genomic approaches to explore the possible molecular and cellular mechanisms involved in the protective effects of MT against DOX cardiotoxicity. MT-Ⅰ/Ⅱ null (MT-/-) mice and corresponding wild-type mice (MT+/+) were administrated with a single dose of DOX (15 mg/kg, i.p.) or an equal volume of saline. Animals were sacrificed on the 4th day after DOX administration and samples were collected for further analyses. Global gene expression profiles of cardiac mRNA from two genotype mice revealed that 381 characteristically MT-responsive genes were identified between MT+/+ mice and MT-/- mice in response to DOX, including fos, ucp3, car3, atf3, map3k6, etc.. Functional analysis implied MAPK signaling pathway, p53 signaling pathway, Jak-STAT signaling pathway, PPAR signaling pathway, Wnt signaling pathway, etc. might be involved to mediate the protection of DOX cardiomyopathy by MT. Results from the present study not only validated the previously reported possible mechanisms of MT protection against DOX toxicity, but also provided new clues into the molecular mechanisms involved in this process.

ORGANISM(S): Mus musculus

PROVIDER: GSE23598 | GEO | 2013/08/10

SECONDARY ACCESSION(S): PRJNA131741

REPOSITORIES: GEO

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Global gene expression profiles of MT knockout and wild-type mice in the condition of doxorubicin-induced cardiomyopathy

Project description:The present study was designed using MT knockout mice in concert with genomic approaches to explore the possible molecular and cellular mechanisms involved in the protective effects of MT against DOX cardiotoxicity. MT-M-bM-^EM- /M-bM-^EM-! null (MT-/-) mice and corresponding wild-type mice (MT+/+) were administrated with a single dose of DOX (15 mg/kg, i.p.) or an equal volume of saline. Animals were sacrificed on the 4th day after DOX administration and samples were collected for further analyses. Global gene expression profiles of cardiac mRNA from two genotype mice revealed that 381 characteristically MT-responsive genes were identified between MT+/+ mice and MT-/- mice in response to DOX, including fos, ucp3, car3, atf3, map3k6, etc.. Functional analysis implied MAPK signaling pathway, p53 signaling pathway, Jak-STAT signaling pathway, PPAR signaling pathway, Wnt signaling pathway, etc. might be involved to mediate the protection of DOX cardiomyopathy by MT. Results from the present study not only validated the previously reported possible mechanisms of MT protection against DOX toxicity, but also provided new clues into the molecular mechanisms involved in this process. Male MT+/+ & MT-/- mice (6-8 weeks old) were randomly assigned to treatment or control groups and administrated with a single dose of DOX (15 mg/kg, i.p.) or an equal volume of normal saline solution (NS) respectively. Animals were sacrificed on the 4th day after DOX injection, and samples were collected for further microarray analyses.

2013-08-10 | E-GEOD-23598 | 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

Indusible hepsin overexpression activates TGFβ signaling in a Wap-Myc model of breast cancer

Project description:To test if ectopic overexpression of hepsin (TMPRSS1) induces TGFβ signaling in the context of tumorigenesis, we made use of a previously published tumor syngraft model of Myc-driven breast cancer (Partanen et al., 2012 PMID: 22308451). Wap-Myc mammary tumor cells, which express high Myc levels, were isolated from donor mice, transduced with the pIND21-HPN lentiviral construct that allows doxycycline (DOX)-induced hepsin overexpression, and subsequentially transplanted into recipient mice. Consistent with the notion that hepsin promotes TGFβ signaling, western blot analysis revealed increased phospho-Smad2/3 and upregulation of the TGFβ signaling downstream target SNAIL in Wap-Myc tumors with DOX-induced hepsin overexpression compared to control (-DOX) tumors. RNAseq analysis of these tumors provided additional evidence for TGFβ pathway upregulation by hepsin as the most significantly upregulated gene signatures corresponded to the TGFβ signaling pathway. The largest cluster of gene signatures affected by hepsin overexpression, however, was related to the ECM and integrins.

2021-08-04 | GSE164510 | GEO

Transgenerational inheritance of mitochondrial stress adaptation in C. elegans

Project description:Using Caenorhabditis elegans to investigate environmental cues-induced mitochondrial dysfunction, we found that exposure to electron transport chain (ETC) inhibitors at the parental generation initiates the transmission of heritable information to descendants and make descendants stress-adaptive. This mitochondrial stress adaptation phenotype can persist for at least three generations. Animals lacking histone H3K4me3 chromatin modifiers, or the methyltransferase of N6-methyldeoxyadenosine (6mA), lose the ability to initiate stress adaptation in progeny. H3K4me3 plays a role upstream of 6mA, while both mark promoter regions of mitochondrial unfolded protein response (UPR mt ) genes and activate the UPR mt pathway to alleviate mitochondrial damage.

2017-07-26 | GSE85835 | GEO

Changes in gene expression caused by loss of Med1 in the mouse prostate

Project description:MED1 is a transcriptional coactivator for gene-specific activators involved in growth and development, we were interested in identifying MED1 target genes potentially involved in prostate development by cDNA microarray. Med1 was conditional knocked out in mice prostate. We performed cDNA microarray with two sets: (1) RNA isolated from three WT ventral prostates and three MT ventral prostates; (2) RNA isolated from three WT lateral prostates and three MT lateral prostates. We used microarrays to detail the global programme of gene expression underlying how Med1 was involved in mice prostate development by regulating targeted genes expression 12 mice prostate samples were divided into two groups: (1) three WT ventral prostates and three MT ventral prostates; (2) three WT lateral prostates and three MT lateral prostates.

2015-05-22 | E-GEOD-69124 | biostudies-arrayexpress

Thrombopoietin (TPO) protects against heart damage induced by doxorubicin and infarction in rat models

Project description:In order to examine the mechanism of TPO on cardiac protection against DOX damage, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to delineate the TPO cardioprotective mechanism against DOX-induced cardiomyopathy

2010-12-29 | GSE15449 | GEO

m6A Demethylase ALKBH5 attenuates doxorubicin-induced cardiotoxicity via posttranscriptional stabilization of Rasal3

Project description:The clinical application of anthracyclines such as doxorubicin (DOX) is limited due to their cardiotoxicity. N6-methyladenosine (m6A) plays an essential role in numerous biological processes. However, the roles of m6A and m6A demethylase ALKBH5 in DOX-induced cardiotoxicity (DIC) remain unclear. In this research, DIC models were constructed using Alkbh5-knockout (KO), Alkbh5-knockin (KI), and Alkbh5-myocardial-specific knockout (ALKBH5flox/flox, αMyHC-Cre) mice. Cardiac function and DOX-mediated signal transduction were investigated. As a result, both Alkbh5 whole-body KO and myocardial-specific KO mice had increased mortality, decreased cardiac function, and aggravated DIC injury with severe myocardial mitochondrial damage. Conversely, ALKBH5 overexpression alleviated DOX-mediated mitochondrial injury, increased survival, and improved myocardial function. Mechanistically, ALKBH5 regulated the expression of Rasal3 in an m6A-dependent manner through posttranscriptional mRNA regulation and reduced Rasal3 mRNA stability, thus activating RAS3, inhibiting apoptosis through the RAS/RAF/ERK signaling pathway, and alleviating DIC injury. These findings indicate the potential therapeutic effect of ALKBH5 on DIC.

2023-03-08 | GSE224215 | GEO

Comprehensive circRNA expression profile and construction of circRNAs-related ceRNA network in a mouse model of autism

Project description:Purpose: We aimed to detected the circRNA expression profile and constructed a circRNA-based competing endogenous RNA (ceRNA) network in autism. Methods:Valproate acid was used to establish an in vivo model of autism in mice. circRNAs in autism group was identified by RNA sequencing. The expression of circRNAs were detected by real-time PCR. Module analysis was conducted followed by GO and KEGG pathway enrichment analysis. Results: A total of 1059 differentially expressed circRNAs (477 upregulated and 582 downregulated) in autism group. The expression of novel_circ_015779 and novel_circ_035247 were detected by real-time PCR. A ceRNA network based on altered circRNAs was established, with 9715 nodes and 150408 edges. The top three modules were all correlated with autism-related pathways involving ‘TGF-beta signaling pathway’, ‘Notch signaling pathway’, ‘MAPK signaling pathway’, ‘long term depression’, ‘thyroid hormone signaling pathway’, etc. Conclusions: The present study reveals a novel circRNA involved mechanisms in the pathogenesis of autism.

2020-12-29 | GSE163904 | GEO

Transcriptome Alterations in ASMT Knockout-Induced Depression-Like Behaviors and Exercise Effects

Project description:Sleep disorder caused by abnormal circadian rhythm is one of the main symptoms and risk factors of depression. N-acetylserotonin methyltransferase (ASMT), the last rate-limiting enzyme of melatonin (MT, a known hormone regulating circadian rhythms), has been reportedly associated with depression. Exercise can regulate circadian rhythm and play an important role in depression treatment. Recently, gene chip has been widely used in depression research. In the present study, we showed that ASMT knockout induced depression-like behaviors, which were ameliorated by swimming exercise. Moreover, swimming exercise increased serum levels of MT and 5-HT in ASMT knockout mice. In addition, transcriptome analysis identified 10 differentially expressed genes (DEGs) in KO mice compared with WT mice, and 29 DEGs in KO mice after swimming exercise. Among the DEGs, the direction and magnitude of change in Eps8l1 and Plcb2 were confirmed by qRT-PCR partly. Subsequent bioinformatic analysis showed that p53 signaling pathway, long-term depression and estrogen signaling pathway were enriched significantly. In the protein-protein interaction (PPI) networks, Mpp1 and Pidd1 were hub genes. These findings may provide new targets for the treatment of circadian rhythm-associated depression.

2022-03-06 | GSE197888 | GEO

Phosphodiesterase 10A inactivation protects against doxorubicin-induced cardiotoxicity and concomitantly inhibits tumor growth

Project description:Phosphodiesterase 10A (PDE10A), by degrading cAMP/cGMP, play critical roles in cardiovascular biology/disease. Cardiotoxicity is a clinical complication of chemotherapy. We aim to determine the role of PDE10A in cancer growth and cardiotoxicity induced by doxorubicin (DOX), a chemotherapy drug. We found that PDE10A deficiency/inhibition alleviated DOX-induced cardiotoxicity in C57Bl/6J mice, including myocardial atrophy, apoptosis, and dysfunction. RNAseq study revealed several PDE10A-regulated signaling associated with DOX-induced cardiotoxicity. In cancer cells, PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX in various cancer-cell lines. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protected against DOX-induced cardiotoxicity. In isolated cardiomyocytes (CMs), PDE10A contributed to DOX-induced CM death via promoting mitochondrial dysfunction, and to CM atrophy via potentiating foxo3 signaling. Collectively, our study elucidates a novel role for PDE10A in cardiotoxicity and cancer growth in vitro and in vivo, and suggest that PDE10A inhibition may represent a novel strategy in cancer therapy.

2023-06-22 | GSE224157 | GEO

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