Activation of CISD2 as a Protective Strategy against Doxorubicin-Induced Cardiotoxicity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE307421 | GEO | 2025/09/09
REPOSITORIES: GEO
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Project description:Activation of CISD2 as a Protective Strategy against Doxorubicin-Induced Cardiotoxicity
| PRJNA1321594 | ENA
Project description:Doxorubicin is a widely used and effective anthracycline chemotherapy drug, which use is limited due to its cardiotoxic side effects. We show that gene therapy with AAV-VEGF-B can inhibit the doxorubicin-induced cardiac atrophy and whole body cachexia.
2016-09-30 | GSE81448 | GEO
Project description:Background: Cardiomyocyte loss occurs in acute and chronic cardiac injury, including cardiotoxicity due to chemotherapeutic agents such as doxorubicin, and contributes to development of heart failure. There is a pressing need for cardiac-specific therapeutics that prevent the cardiac complications of chemotherapy without compromising efficacy by directly targeting cardiomyocyte loss. Objectives: We employed massively parallel combinatorial genetic screening to search for miRNA combinations that promote cardiomyocyte survival. Methods: Combinatorial genetics en masse (CombiGEM) screening in a cardiomyocyte cell line was followed by validation studies in the original cell type as well as primary cardiomyocytes to search for miRNA combinations that promote survival under various stress conditions. The top candidate combination was tested human iPSC-derived cardiomyocyte and in vivo mouse and developing zebrafish models of doxorubicin cardiotoxicity. RNA sequencing and in silico miRNA target prediction provided insight into possible mechanisms. Results: CombiGEM screens and validation experiments identified multiple miRNA combinations that protected cardiomyocytes from doxorubicin in vitro. The most effective miRNA combination (miR-222 + miR-455) appeared to act synergistically and had protective effects in both murine and zebrafish in vivo doxorubicin cardiotoxicity models. RNA sequencing data revealed synergistic and additive regulation of mechanistically relevant genes and biological processes, including mitochondrial homeostasis, cellular respiration, DNA replication/damage response, oxidative and ER stress, angiogenesis, muscle contraction/relaxation, and others. Conclusions: We identified miR-222 and miR-455 as a combination with potential therapeutic applications for cardioprotection. The results of this study further our knowledge of the cardiac effects of individual miRNAs and their combinations and demonstrate the value of the CombiGEM approach for discovery of cardioprotective combinatorial therapeutic candidates.
2025-07-09 | GSE282974 | 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: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:Doxorubicin (Dox) poses a considerable threat to patients owing to its cardiotoxicity, thus limiting its clinical utility. Optimal cardioprotective intervention strategies are needed to suppress tumor growth but also minimize cardiac side effects. Here, we showed that tVNS improved the imbalanced autonomic tone, ameliorated impaired cardiac function and fibrosis, attenuated myocyte apoptosis, and mitochondrial dysfunction compared to those in the Dox group. The beneficial effects were attenuated by methyllycaconitine citrate (MLA). The transcript profile revealed that there were 248 differentially expressed genes and the protection of tVNS and retardation of MLA were related to inflammatory response and NADPH oxidase activity. In addition, tVNS synergizing with Dox inhibited tumor growth and lung metastasis and promoted apoptosis of tumor cells in an anti-tumor immunity manner. These results indicated that non-invasive neuromodulation can play a dual role in preventing Dox-induced cardiotoxicity and suppressing tumor growth through inflammation and oxidative stress.
2024-01-28 | GSE253959 | GEO
Project description:Doxorubicin (DOX) induces oxidative stress leading to cardiotoxicity. Diosgenin, a steroidal saponin of Dioscorea opposita, has been reported to have antioxidant activity. Our study was aimed to find out the protective effect of diosgenin against DOX-induced cardiotoxicity in mice. DOX treatment led to a significant decrease in the ratio of heart weight to body weight, and increases in the blood pressure and the serum levels of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and creatine kinase myocardial bound (CK-MB), markers of cardiotoxicity. In the heart tissue of the DOX-treated mice, DOX reduced activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), were recovered by diosgenin. Diosgenin also decreased the serum levels of cardiotoxicity markers, cardiac levels of thiobarbituric acid relative substances (TBARS) and reactive oxygen species (ROS), caspase-3 activation, and mitochondrial dysfunction, as well as the expression of nuclear factor kappa B (NF-κB), an inflammatory factor. Moreover, diosgenin had the effects of increasing the cardiac levels of cGMP via modulation of phosphodiesterase-5 (PDE5) activity, and in improving myocardial fibrosis in the DOX-treated mice. Molecular data showed that the protective effects of diosgenin might be mediated via regulation of protein kinase A (PKA) and p38. Our data imply that diosgenin possesses antioxidant and anti-apoptotic activities, and cGMP modulation effect, which in turn protect the heart from the DOX-induced cardiotoxicity.
| S-EPMC4488824 | biostudies-literature
Project description:Cardioprotection of dexrazoxane (DZR) against doxorubicin (DOX)-induced cardiotoxicity is contentious and the indicator is controversial. A pairwise comparative metabolomics approach was used to delineate the potential metabolic processes in the present study. Ninety-six BALB/c mice were randomly divided into two supergroups: tumor and control groups. Each supergroup was divided into control, DOX, DZR, and DOX plus DZR treatment groups. DOX treatment resulted in a steady increase in 5-hydroxylysine, 2-hydroxybutyrate, 2-oxoglutarate, 3-hydroxybutyrate, and decrease in glucose, glutamate, cysteine, acetone, methionine, asparate, isoleucine, and glycylproline.DZR treatment led to increase in lactate, 3-hydroxybutyrate, glutamate, alanine, and decrease in glucose, trimethylamine N-oxide and carnosine levels. These metabolites represent potential biomarkers for early prediction of cardiotoxicity of DOX and the cardioprotective evaluation of DZR.
| S-EPMC5224977 | biostudies-literature
Project description:Druggable genome of CRISPRi/a sgRNA libraries for druggable genes protecting doxorubicin induced cardiomyocyte toxicity using human induced pluripotent stem cell (iPSC) derived cardiomyocytes.
2024-09-01 | GSE276161 | GEO
Project description:The chemotherapeutic effect of doxorubicin (Dox) is limited by cumulative dose-dependent cardiotoxicity in cancer survivors. Dexrazoxane (DRZ) is approved to prevent Dox-induced cardiotoxicity. Humanin and its synthetic analog HNG have a cytoprotective effect on the heart. To investigate the cardioprotective efficacy of HNG alone or in combination with DRZ against Dox-induced cardiotoxicity, 80 adult male mice were randomly divided into 8 groups to receive the following treatments via intraperitoneal injection: saline dailym HNG (5 mg/kg) daily, DRZ (60 mg/kg) weekly, Dox (3 mg/kg) weekly, DRZ + HNG, Dox + HNG, Dox + DRZ, and Dox + HNG + DRZ. Echocardiograms were performed before and at 4, 8, and 9.5 wk after the beginning of treatment. All mice were euthanized at 10 wk. In the absence of Dox, HNG, DRZ, or DRZ + HNG had no adverse effect on the heart. Dox treatment caused decreases in ejection fraction and cardiac mass and increases in cardiomyocyte apoptosis and intracardiac fibrosis. HNG or DRZ alone blunted the Dox-induced decrease in left ventricle posterior wall thickness and modestly ameliorated the Dox-induced decrease in ejection fraction. HNG + DRZ significantly ameliorated Dox-induced decreases in ejection function, cardiac fibrosis, and cardiac mass. Using a targeted analysis for the mitochondrial gene array and protein expression in heart tissues, we demonstrated that HNG + DRZ reversed DOX-induced altered transcripts that were biomarkers of cardiac damage and uncoupling protein-2. We conclude that HNG enhances the cardiac protective effect of DRZ against Dox-induced cardiotoxicity. HNG + DRZ protects mitochondria from Dox-induced cardiac damage and blunts the onset of cardiac dysfunction. Thus, HNG may be an adjuvant to DRZ in preventing Dox-induced cardiotoxicity. NEW & NOTEWORTHY Doxorubicin (Dox) is commonly used for treating a wide range of human cancers. However, cumulative dosage-dependent carditoxicity often limits its clinical applications. We demonstrated in this study that treating young adult male mice with synthetic humanin analog enhanced the cardiac protective effect of dexrazoxane against chemotherapeutic agent Dox-induced cardiac dysfunction. Thus, humanin analog can potentially serve as an adjuvant to dexrazoxane in more effectively preventing Dox-induced cardiac dysfunction and cardiomyopathy.
| S-EPMC6734085 | biostudies-literature