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
Similar Datasets
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:Xijiao Dihuang decoction protects against sepsis-induced cardiac dysfunction
| PRJNA891339 | ENA
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:Cardiac resident MerTK+ macrophages exert multiple protective roles post-ischemic injury, however, the mechanisms regulating their fate are not fully understood. Here we show that GAS6-inducible transcription factor ATF3 prevents apoptosis of MerTK+ macrophages after ischemia-reperfusion (IR) injury, by repressing the transcription of multiple genes involved in type I interferon expression (Ifih1 and Infb1) and apoptosis (Apaf1). Mice lacking ATF3 in cardiac macrophages or myeloid cells showed excessive loss of MerTK+ cardiac macrophages, poor angiogenesis, and worse heart dysfunction post-IR, which were rescued by the transfer of MerTK+ cardiac macrophages. GAS6 administration improved cardiac repair in an ATF3-dependent manner. Finally, we showed a negative association of GAS6 and ATF3 expression with the risk of major adverse cardiac events in patients with ischemic heart disease. These results indicate that the GAS6-ATF3 axis has a protective role against IR injury by regulating MerTK+ cardiac macrophage survival/proliferation.
2023-11-07 | GSE247139 | GEO
Project description:Aims: Cardiomyocytes apoptosis is the predominant pathological feature following myocardial infarction (MI) and significantly impacts disease progression and outcomes. Zinc finger NFX1-type containing 1 (ZNFX1), an RNA helicase family member, remains relatively understudied in molecular biology and its role in cardiovascular diseases remains unclear. This study aims to explore the involvement of ZNFX1 in MI and uncover its mechanisms underlying cardiomyocyte apoptosis. Methods and results: Male C57BL/6 mice were administered AAV9-ZNFX1 or AAV9-sh-ZNFX1 with the cTNT promoter via tail vein injection for the purpose of cardiomyocyte-specific ZNFX1 overexpression or knockdown. Concurrently, left anterior descending coronary artery ligation (LAD) was performed to induce MI. Echocardiography was utilized to evaluate the cardiac function. Triphenyl tetrazolium chloride (TTC), Hematoxylin and eosin (HE) and Masson's trichrome staining were used to evaluate the cardiac infarction and cardiac remodeling. TUNEL assay, flow cytometry, western blot and quantitative reverse transcription PCR (qRT-PCR) were employed to evaluate apoptosis. The cardiomyocyte viability was quantified using the CCK-8 assay. RNA sequencing (RNA-seq) and RNA immunoprecipitation assays (RIP) were employed to investigate the interaction between ZNFX1 and apoptosis-associated genes. The expression of ZNFX1 was decreased in MI myocardium and hypoxia-treated cardiomyocytes. Overexpression of ZNFX1 significantly attenuated cardiac dysfunction, reduced infarct size, inhibited collagen deposition and alleviated cardiac hypertrophy which was ascribed to MI in mice, whereas knockdown of ZNFX1 produced the opposite effects. RNA-seq identified apoptosis as a possible regulated pathway of ZNFX1, overexpression of ZNFX1 represses the cardiomyocyte apoptosis that gives rise to MI while knockdown of ZNFX1 deteriorates it. Mechanically, ZNFX1 binds with mRNA of apoptosis genes that contain highly structured 3'UTR and prompts their decay. Conclusion: ZNFX1 plays a protective role in MI by degrading mRNA of apoptosis-related genes, which often possess highly structured 3'UTRs. This highlights ZNFX1 as a potential novel molecular target for treating cardiac dysfunction associated with MI. Keywords: ZNFX1, apoptosis, mRNA stability, helicase activity, UPF1, myocardial infarction
2025-06-25 | GSE272829 | GEO
Project description:Aims: Cardiomyocytes apoptosis is the predominant pathological feature following myocardial infarction (MI) and significantly impacts disease progression and outcomes. Zinc finger NFX1-type containing 1 (ZNFX1), an RNA helicase family member, remains relatively understudied in molecular biology and its role in cardiovascular diseases remains unclear. This study aims to explore the involvement of ZNFX1 in MI and uncover its mechanisms underlying cardiomyocyte apoptosis. Methods and results: Male C57BL/6 mice were administered AAV9-ZNFX1 or AAV9-sh-ZNFX1 with the cTNT promoter via tail vein injection for the purpose of cardiomyocyte-specific ZNFX1 overexpression or knockdown. Concurrently, left anterior descending coronary artery ligation (LAD) was performed to induce MI. Echocardiography was utilized to evaluate the cardiac function. Triphenyl tetrazolium chloride (TTC), Hematoxylin and eosin (HE) and Masson's trichrome staining were used to evaluate the cardiac infarction and cardiac remodeling. TUNEL assay, flow cytometry, western blot and quantitative reverse transcription PCR (qRT-PCR) were employed to evaluate apoptosis. The cardiomyocyte viability was quantified using the CCK-8 assay. RNA sequencing (RNA-seq) and RNA immunoprecipitation assays (RIP) were employed to investigate the interaction between ZNFX1 and apoptosis-associated genes. The expression of ZNFX1 was decreased in MI myocardium and hypoxia-treated cardiomyocytes. Overexpression of ZNFX1 significantly attenuated cardiac dysfunction, reduced infarct size, inhibited collagen deposition and alleviated cardiac hypertrophy which was ascribed to MI in mice, whereas knockdown of ZNFX1 produced the opposite effects. RNA-seq identified apoptosis as a possible regulated pathway of ZNFX1, overexpression of ZNFX1 represses the cardiomyocyte apoptosis that gives rise to MI while knockdown of ZNFX1 deteriorates it. Mechanically, ZNFX1 binds with mRNA of apoptosis genes that contain highly structured 3'UTR and prompts their decay. Conclusion: ZNFX1 plays a protective role in MI by degrading mRNA of apoptosis-related genes, which often possess highly structured 3'UTRs. This highlights ZNFX1 as a potential novel molecular target for treating cardiac dysfunction associated with MI. Keywords: ZNFX1, apoptosis, mRNA stability, helicase activity, UPF1, myocardial infarction
2025-06-25 | GSE273385 | 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.
2024-06-01 | GSE260663 | GEO
Project description:SARS-CoV2 infection leads to cardiac injury and dysfunction in 20-30% of hospitalized patients and higher rates of mortality in patients with pre-existing cardiovascular disease. Inflammatory factors released as part of the 'cytokine storm' are thought to play a critical role in cardiac dysfunction in severe COVID-19 patients. Here we use human cardiac organoid technology combined with high sensitivity phosphoproteomics and single nuclei RNA sequencing to identify inflammatory targets inducing cardiac dysfunction. This new pipeline allowed rapid progress and identification of putative therapeutics. We identify a novel interferon-gamma driven BRD4 (bromodomain protein 4)-fibrosis/iNOS axis as a key intracellular mediator of inflammation-induced cardiac dysfunction. This axis is therapeutically targetable using BRD4 inhibitors, which promoted full recovery of function in human cardiac organoids and prevented severe inflammation and death in a cytokine-storm mouse model. The BRD inhibitor INCB054329 was the most efficacious, and is a prime candidate for drug repurposing to attenuate cardiac dysfunction and improve COVID-19 mortality in humans.
2022-02-21 | PXD020994 | Pride
Project description:C57BL6/J mice were treated with anti-PD-1 for 2 or 4 weeks, or with isotype control antibody. In echocardiography, cardiac dysfunction was seen both after 2 and 4 weeks, with decreased ejection fraction and left ventricular dilation. Bulk RNA sequencing of the hearts after treatment was performed to identify the mechanisms of anti-PD-1-induced cardiac dysfunction.
2022-12-03 | E-MTAB-12388 | biostudies-arrayexpress