CIRBP safeguards against chemotherapeutics-induced cardiac apoptosis and cardiotoxicity via dampening OGF/OGFR signal
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Cihang Liu
PROVIDER: PXD026052 | iProX | Mon May 17 00:00:00 BST 2021
REPOSITORIES: iProX
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Project description:Background: Albeit with well-recorded cytoprotective function, the study of stress protein CIRBP coping with cardiotoxicity during chemotherapy remains obscured. Here we report that CIRBP plays a critical role in safeguarding against chemo-induced cardiac apoptosis and dysfunction. Methods: Treating the immortalized human ventricular myocytes (T0519) and neonatal rat ventricular myocytes (NRVMs) with three regular chemotherapeutics (DOX/Cisplatin/5-FU), and DOX-induced cardiotoxic mouse model were leveraged to explore the cardioprotection of CIRBP during chemotherapy. We took advantage of AAV9 carrying CIRBP or shCIRBP expressive cassette under cTNT promoter to interfere with cardiac CIRBP expression. A conjoint analysis of transcriptomics and proteomics was performed within T0519 to identify the latent effector of CIRBP in regulating cardiomyocyte apoptosis. By contrast with the pan-opioid receptor Alvimopan (ALV), OGFR blocker Naltrexone (NTX) was introduced to disrupt CIRBP-OGFR signaling in an attempt to provide new insight in formulating efficacious cardioprotective scheme for tumor patients. Results: We discovered that CIRBP deficiency is involved in in-vivo and in-vitro cardiomyocyte apoptosis triggered by chemotherapeutic agents. Ectopic delivery of CIRBP in mouse myocardium significantly mitigates doxorubicin-induced cardiac apoptosis and malfunction. Opioid growth factor receptor (OGFR) was further highlighted as CIRBP downstream effector responsible for cardiomyocyte chemotherapeutical apoptosis. Mechanistically, CIRBP interacts with OGFR mRNA and represses OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced apoptosis relies largely on the regulation of CIRBP on OGFR. Naltrexone, an antagonist targeting OGFR of potency as well as certain opioid receptors, successfully rescues CIRBP ablation-rendered susceptibility to cardiac apoptosis and dyshomeostasis when exposed to DOX; while another antagonist Alvimopan, merely acting on opioid receptors, does not. Conclusions: Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction via dampening OGF/OGFR axis, shedding new light on the cardioprotection of tumor patients subjected to chemotherapy.
2022-12-06 | GSE175747 | GEO
Project description:Background - Cardiac microRNAs (miRNAs) could be released into circulation thus becoming circulating cardiac miRNAs, which are increasingly recognized as noninvasive and readily accessible biomarker for multiple heart diseases. A global loss of cardiac miRNAs due to dicer or dgcr8 depletion has been reported to lead to dilated cardiomyopathy (DCM). However, DCM-associated circulating miRNAs (DACMs) and their roles in regulating DCM progression remain largely unexplored. Methods and Results - Through miRNA sequencing of human plasma procured from DCM patients and healthy control people, DCM was characterized with a unique expression pattern for circulating miRNAs. Among them, miR-26a-5p, miR-30c-5p, miR-126-5p, and miR-126-3p were all identified with dramatic reductions in DCM mouse myocardium as in the plasma of DCM patients. FOXO3, highlighted as a predicted common target gene, was experimentally demonstrated to be repressed within cardiomyocytes by these miRNAs except miR-26a-5p. Mechanistically, miRNA combination (miR-30c-5p, miR-126-5p, and miR-126-3p) significantly attenuated FOXO3-induced apoptosis and autophagy observed in cardiomyocytes as well as in DCM murine heart. Cardiac-specific knockout of FOXO3 conspicuously mitigated myocardial apoptosis and autophagy in DCM development. Moreover, stymieing the interaction between these miRNAs and FOXO3 mRNA extremely crippled the cardioprotection of these miRNAs against DCM progression. Cardiac miRNA-FOXO3 axis plays a pivotal role in safeguarding against myocardial apoptosis and autophagy, thereby maintaining cardiac homeostasis and potently preventing DCM development. These findings may provide serological clues for the noninvasive diagnosis of DCM in the future, and unambiguously shed new light on DCM pathogenesis and associated therapeutic targets
2022-07-31 | GSE209991 | GEO
Project description:CIRBP safeguards against chemotherapeutics-induced cardiac apoptosis and cardiotoxicity via dampening OGF/OGFR signal
| PRJNA733480 | ENA
Project description:Chemo-resistance is the major cause of death in advanced prostate cancer (PCa), especially in metastatic PCa (mPCa). However, the molecular mechanisms behind chemo-resistance of PCa have not been clarified so far. Here we found GADD45B was significantly low expressed in metastasis PCa and it could promote chemotherapy sensitivity. So we further constructed GADD45B overexpressed cell line to investigate the possible mechanism.
2021-07-01 | E-MTAB-10704 | biostudies-arrayexpress
Project description:FAT10 is a new member of the ubiquitin-like protein family with yet-to-be defined biological functions in the heart. Our objective was to determine the role of FAT10 in the heart. FAT10 is expressed in the normal human and murine hearts, as detected by qPCR and Western blotting. Expression of FAT10 is increased in the heart at the border zone of myocardial infarction and in cultured neonatal rat cardiac myocytes (NRCM) subjected to hypoxia/reoxygenation (H/R) stress. Lentiviral-mediated overexpression of FAT10 in NRCM reduced p53 (TP53) and its target miR-34a levels, while BCL2 level, a target of miR-34a, was increased and BAX level, a pro-apoptotic protein, was reduced. These changes were associated with reduced apoptosis, detected by FACS analysis of annexin-V expression and TUNEL assay, in response to H/R injury. Knock down of FAT10 by shRNA targeting had the opposite effects. Likewise, lentiviral mediated expression of miR-34a was associated with reduced BCL2 and increased BAX levels in NRCM and also reversed changes in BCL-2 and BAX levels observed upon over-expression of FAT10. Treatment of NRCM with proteasome inhibitor MG132 increased p53 and miR-34a levels and reduced BLC2/BAX ratio. These changes were not reversed upon over-expression of FAT10. Thus, FAT10 is upregulated in the heart and NRCM in response to H/R stress, which protects cardiac myocytes against apoptosis. The anti-apoptotic effects of FAT10 are associated with suppression of p53, probably through fatylation and proteasomal degradation, reduced miR-34a expression, and a shift in the BCL2/BAX proteins against apoptosis. Thus, FAT10 is a cardioprotective protein.
| S-EPMC3646899 | biostudies-literature
Project description:1.1 Introduction Cardiac fibrosis occurs in a wide range of cardiac diseases and is characterised by the transdifferentiation of cardiac fibroblasts into myofibroblasts these cells produce large quantities of extracellular matrix, resulting in myocardial scar. The profibrotic process is multi-factorial, meaning identification of effective treatments has been limited. The antifibrotic effect of the bile acid ursodeoxycholic acid (UDCA) is established in cases of liver fibrosis however its mechanism and role in cardiac fibrosis is less well understood. 1.2 Methods In this study, we used cellular models of cardiac fibrosis and living myocardial slices to characterise the macroscopic and cellular responses of the myocardium to UDCA treatment. We complemented this approach by conducting RNA-seq on cardiac fibroblasts isolated from dilated cardiomyopathy patients. This allowed us to gain insights into the mechanism of action and explore whether the IL-11 and TGFβ/ WWP2 profibrotic networks are influenced by UDCA. Finally, we used fibroblasts from a TGR5 KO mouse to confirm the mechanism of action. 1.3 Results and Discussion We found that UDCA reduced myofibroblast markers in rat and human fibroblasts and in living myocardial slices, indicating its antifibrotic action. Furthermore, we demonstrated that the treatment of UDCA successfully reversed the profibrotic IL-11 and TGFβ/ WWP2 gene networks. We also show that TGR5 is the most highly expressed UDCA receptor in cardiac fibroblasts. Utilising cells isolated from a TGR5 knock-out mouse, we identified that the antifibrotic effect of UDCA is attenuated in the KO fibroblasts. This study combines cellular studies with RNA-seq and state-of-the-art living myocardial slices to offer new perspectives on cardiac fibrosis. Our data confirm that TGR5 agonists, such as UDCA, offer a unique pathway of action for the treatment of cardiac fibrosis. Medicines for cardiac fibrosis have been slow to clinic and have the potential to be used in the treatment of multiple cardiac diseases. UDCA is well tolerated in the treatment of other diseases, indicating it is an excellent candidate for further in-human trials.
2024-11-30 | E-MTAB-14602 | biostudies-arrayexpress
Project description:Gene profiling analysis was performed to investigate the molecular basis for the cardioprotective effect of cardiac-specific LXRα overexpression.
2015-05-30 | GSE69355 | GEO
Project description:Esophageal squamous cell carcinoma (ESCC) is a serious cancer with a poor prognosis and a high recurrence rate after chemotherapy, which is a major clinical challenge. To elucidate the molecular basis of chemotherapy (chemo)-resistance and develop methods to effectively eliminate chemo-resistant tumor clones, we established a cancer organoid model from 24 ESCC patients of various stages, ages, and treatments. These ESCCOs recapitulated most oncogenic mutations of primary ESCC tissues and had tumorigenic properties upon xenografting. Each organoid line differs in its responsiveness to 5-fluorouracil (5-FU) and cisplatin (CDDP), chemotherapeutic agents commonly used to treat ESCC patients, with 7 lines exhibiting potent chemo-resistance. Importantly, these chemo-resistant ESCCOs had enhanced expression of genes involved in antioxidant stress response pathways and increased chromatin accessibility of their genomic loci, compared to chemo-sensitive ESCCOs, and these genes became useful biomarkers that can stratify chemo-resistant ESCC in histopathological specimens.
2025-02-25 | GSE269447 | GEO
Project description:Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease but the significance of HINT2 in cardiac hypertrophy remains unknown. Therefore, the current study aims to determine the role of HINT2 in cardiac remodeling. HINT2 expression was found to be lower in failing hearts and hypertrophic cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocytes hypertrophy and cardiac dysfunction in response to stress. Conversely, the deficiency of HINT2 in the heart of mice resulted in a worsened hypertrophic phenotype. Further analysis indicated that the upregulated genes were primarily associated with the oxidative phosphorylation and mitochondrial complex I pathway in the HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 upregulated the expression of NDUFs genes. In cellular studies, the protective effect of overexpressing HINT2 was nullified. Lastly, we predicted that THRB might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac hypertrophy by depending on the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic intervention for reducing cardiac remodeling.
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2023-11-07 | GSE247139 | GEO