Self-maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-induced Cardiomyopathy through the SR-A1-c-Myc Axis
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ABSTRACT:
PROVIDER: PRJNA622239 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11459527_1.fastq.gz | Fastqsanger.gz | |||
| SRR11459527_2.fastq.gz | Fastqsanger.gz | |||
| SRR11459528_1.fastq.gz | Fastqsanger.gz | |||
| SRR11459528_2.fastq.gz | Fastqsanger.gz | |||
| SRR11459529_1.fastq.gz | Fastqsanger.gz |
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Project description:Rationale: Doxorubicin-induced cardiomyopathy (DiCM) is a significant cause of heart failure and mortality in cancer patients, in which macrophage-orchestrated inflammation serves as an essential pathogenic mechanism. However, the specific roles of tissue-resident and monocyte-derived macrophages in DiCM remain poorly understood. Objective: Uncovering the origins, phenotypes, and functions of proliferative cardiac resident macrophages and mechanistic insights into the self-maintenance of cardiac macrophage during DiCM progression. Methods and Results: Mice were administrated with doxorubicin to induce cardiomyopathy. Dynamic changes of resident and monocyte-derived macrophages were examined by lineage tracing, parabiosis, and bone marrow transplantation. We found that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated the whole DiCM pathological process and impaired cardiac function. In contrast, cardiac resident macrophages were vulnerable to doxorubicin insult. The survived resident macrophages exhibited enhanced proliferation and conferred a reparative role. Global or myeloid specifically ablation of class A1 scavenger receptor (SR-A1) inhibited proliferation of cardiac resident reparative macrophages and therefore exacerbated cardiomyopathy in DiCM mice. Importantly, the detrimental effect of macrophage SR-A1 deficiency was confirmed by transplantation of GFP+ wild type bone marrow. At the mechanistic level, we show that c-Myc, a key transcriptional factor for the SR-A1-P38-SIRT1 pathway, mediated the effect of SR-A1 in reparative macrophage proliferation in DiCM. Conclusions: The SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.
2023-03-31 | GSE147834 | GEO
Project description:Metastasis is the key determinant of poor prognosis for advanced-stage NSCLC patients. Although an important contributor to metastasis is cross-talk between tumor-associated macrophages (TAMs) and tumor cells, its regulation is not fully understood. Expressed primarily in macrophages, scavenger receptor A1 (SR-A1) has been associated with lung tumorigenesis. Here, the mechanistic basis for the involvement of SR-A1 in lung cancer prognosis was investigated using population genetics, transcriptomics, and functional analyses. SR-A1 genetic variants were investigated for possible association with survival of advanced-stage NSCLC patients in the Harvard Lung Cancer Study cohort. Two SNPs (rs17484273, rs1484751) in SR-A1 were significantly associated with poor overall survival of NSCLC patients. Further, data from The Cancer Genome Atlas showed a considerable down-regulation of SR-A1 in lung tumor tissues. The association of SR-A1 with prognosis was validated in animal models in the context of lung cancer metastasis. Macrophages derived from SR-A1 knockout mice accelerated metastasis in a lung cancer mouse model. On the other hand, tumor cell seeding, migration, and invasion as well as macrophage accumulation in lung cancer tissue were enhanced in SR-A1 knockout mice. Furthermore, SR-A1 deficiency promoted up-regulation of serum amyloid A1 (SAA1) in macrophages, which appeared to be mediated by MAPK/Ikappa-B/NF-kappaB signaling. Further, SAA1 exposure promoted tumor cell invasion and macrophage migration in vitro and in vivo, but these effects were blocked by administration of an anti-SAA1 antibody. These findings suggest that SR-A1 may suppress lung cancer metastasis by down-regulating SAA1 production in macrophages.
2019-06-16 | GSE83473 | GEO
Project description:To further development of our gene expression approach to biodosimetry, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish differentially changed genes between wt and SR-A1-/- murine aortas.
2023-05-28 | GSE226304 | GEO
Project description:Doxorubicin as a commonly used anthracycline has become the cornerstone of chemotherapy in a wide range of cancers owing to its high efficacy. However, clinical applications of doxorubicin are limited mainly due to its toxic effects on myocardium but the pathogenic mechanism of doxorubicin-induced cardiomyopathy are poorly understood. ADAM17 is known as tumor necrosis factor α converting enzyme (TACE), and the cleavage of TNF-α by ADAM17 is a prerequisite for pro-inflammatory TNF-α activity, which raises a possibility that inhibition of ADAM17 may exert a beneficial effect on disease processes where TNF-α plays an essential role. Our previous research has shown that cardiomyocyte specific knockout of ADAM17 improves diabetic cardiomyopathy by modulating cardiomyocyte apoptosis. However, the relationship between ADAM17 and doxorubicin-induced cardiomyopathy is unclear.Through RNA sequencing analysis, we observed significant changes in the TNF signaling pathway genes in the heart tissue of mice with or without cardiomyocyte ADAM17 knockout.
2024-09-10 | GSE276325 | GEO
Project description:Aims: Hippo signalling is an evolutionarily conserved pathway that controls organ size by regulating apoptosis, cell proliferation and stem cell self-renewal. Recently, the pathway has been shown to exert powerful growth regulatory activity in cardiomyocytes. However, the functional role of this stress- and cell death-related pathway in the human heart and cardiomyocytes is not known. In this study, we investigated the role of the transcriptional co-activators of Hippo signalling, YAP and TAZ, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in response to cardiotoxic agents and investigated the effects of modulating the pathway on cardiomyocyte function and survival. Methods and Results: RNA sequencing analysis of human heart samples with doxorubicin-induced end-stage heart failure and healthy controls showed YAP and ERBB2 (HER2) as upstream regulators of differentially expressed genes correlated with doxorubicin treatment. Thus, we tested the effects of doxorubicin and/or small molecule inhibitor lapatinib on hiPSC-CM in vitro . Using an automated high contentscreen of 96 clinically relevant chemotherapeutic drugs, we showed that doxorubicin induced the highest activation of YAP/TAZ nuclear translocation in both hiPSC-CM and control MCF7 breast cancer cells. The overexpression of YAP rescued doxorubicin- induced cell loss in hiPSC-CM by inhibiting apoptosis and inducing proliferation. In contrast, silencing of YAP and TAZ by siRNAs resulted in elevated mitochondrial membrane potential loss in response to doxorubicin. Human iPSC-CM calcium transients did not change in response to YAP/TAZ silencing. Conclusions: Our results suggest that Hippo signalling is involved in clinical anthracycline-induced cardiomyopathy. Modelling with hiPSC-CM in vitro showed similar responses to doxorubicin as adult cardiomyocytes and revealed a potential cardioprotective effect of YAP in doxorubicin-induced cardiotoxicity.
2022-01-21 | GSE193861 | GEO
Project description:Doxorubicin (Dox) is an effective chemotherapeutic agent against a broad range of tumors. However, a threshold dose of doxorubicin causes an unacceptably high incidence of heart failure and limits its clinical utility. We have established two models of doxorubicin cardiotoxicity in mice: 1) in an acute model, mice are treated with 15mg/kg of doxorubicin once; 2) in a chronic model, they receive 3mg/kg weekly for the first 12 of a total of 18 weeks. Using echocardiography, we have monitored left ventricular function of the mouse hearts during treatment in chronic model and seen the expected development of dilated cardiomyopathy (DCM). Treated mice showed histological abnormalities similar to those seen in patients with doxorubicin cardiomyopathy. To investigate transcriptional regulation in these models, we used a microarray we generated with over 5000 independent cDNA clones from murine heart and skeletal muscle. We have identified genes that respond to doxorubicin exposure in both model systems, and confirmed these results using real-time PCR. In the acute model, a set of genes is regulated early and rapidly returns to baseline levels, consistent with the half-life of doxorubicin. In the chronic model, which mimics the clinical situation much more closely, we identified dysregulated genes that implicate specific mechanisms of cardiac toxicity and may serve as biomarkers of doxorubicin induced dilated cardiomyopathy. Keywords: time course
2005-07-22 | GSE2965 | GEO
Project description:The anthracycline doxorubicin is a commonly used chemotherapeutic drug that induces cardiomyopathy in almost 10% of patients. The aim of this study was to examine the role of the leukocyte-derived enzyme Myeloperoxidase (MPO) in pathogenesis of anthracycline-induced Cardiomyopathy (AICM). We performed proteomics on whole heart tissue of MPO-deficient mice on C57BL/6J background and wildtype (WT) littermates seven days after intravenous injection of the anthracycline Doxorubicin (20 mg/kg bodyweight, dissolved in saline) or saline (NaCl).
2023-08-30 | PXD037524 | Pride
Project description:The clinical application of doxorubicin as a broad-spectrum anti-tumor antibiotic is limited greatly by its cardiotoxicity. Various mechanisms have been studied, but little is known about whether genes or pathways relevant with energy metabolism contributes to doxorubicin-induced cardiomyopathy or not. We used microarrays to detail the global expression profiling of acute cardiomyopathy induced by doxorubicin in wild type or CHIP knockout C57BL/6J mice and discovered distinct classes of changed genes during this process. The whole hearts were selected for RNA extraction and hybridization on Affymetrix microarrays at day 5 after a single intraperitoneal injection of doxorubicin at a dose of 15 mg/kg.
2014-07-23 | E-GEOD-59672 | biostudies-arrayexpress
Project description:The clinical application of doxorubicin as a broad-spectrum anti-tumor antibiotic is limited greatly by its cardiotoxicity. Various mechanisms have been studied, but little is known about whether genes or pathways relevant with energy metabolism contributes to doxorubicin-induced cardiomyopathy or not. We used microarrays to detail the global expression profiling of acute cardiomyopathy induced by doxorubicin in wild type or CHIP knockout C57BL/6J mice and discovered distinct classes of changed genes during this process.
2014-07-23 | GSE59672 | GEO
Project description:Transcriptional co-activators YAP1-TAZ of Hippo signalling in doxorubicin-induced cardiomyopathy
| PRJNA798241 | ENA