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The Cardiac Endothelial Cell cGAS-STING Pathway Promotes Doxorubicin-Induced Cardiotoxicity via CD38-Mediated NAD Decline and Mitochondrial Dysfunction [human]

ABSTRACT: Doxorubicin is an effective chemotherapy drug for treating various types of cancer. However, lethal cardiotoxicity severely limits its clinical use. Recent evidence has indicated that aberrant activation of the cytosolic DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in cardiovascular destruction. Here, we investigate the involvement of this mechanism in doxorubicin-induced cardiotoxicity (DIC).

ORGANISM(S): Homo sapiens

PROVIDER: GSE226115 | GEO | 2023/03/02

REPOSITORIES: GEO

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The Cardiac Endothelial Cell cGAS-STING Pathway Promotes Doxorubicin-Induced Cardiotoxicity via CD38-Mediated NAD Decline and Mitochondrial Dysfunction [mouse]

Project description:Doxorubicin is an effective chemotherapy drug for treating various types of cancer. However, lethal cardiotoxicity severely limits its clinical use. Recent evidence has indicated that aberrant activation of the cytosolic DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in cardiovascular destruction. Here, we investigate the involvement of this mechanism in doxorubicin-induced cardiotoxicity (DIC).

2023-03-02 | GSE226114 | GEO

Human Induced Pluripotent Stem Cells Recapitulate Breast Cancer Patients’ Predilection to Doxorubicin-Induced Cardiotoxicity

Project description:Doxorubicin (Adriamycin) is an anthracycline chemotherapy agent effective in treating a wide range of malignancies1 with a well-established dose-response cardiotoxic side-effect that can lead to heart failure2-4. Even at relatively low cumulative doses of 200–250 mg/m2, the risk of cardiotoxicity is estimated at 7.8% to 8.8%4,5. Doxorubicin-induced cardiotoxicity (DIC) can range from asymptomatic reductions in left ventricular ejection fraction (LVEF) to highly symptomatic heart failure6,7. At present, it is not possible to predict which patients will be affected by DIC or adequately protect patients who are at risk for suffering this devastating side-effect8. Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate individual patients’ predilection to DIC at the single cell level. hiPSC-CMs derived from breast cancer patients who suffered clinical DIC are consistently more sensitive to doxorubicin toxicity, demonstrating decreased cell viability, mitochondrial/metabolic function, calcium handling, and antioxidant pathway gene expression, along with increased reactive oxygen species (ROS) production compared to hiPSC-CMs from patients who did not experience DIC. Together, our data indicate that hiPSC-CMs are a suitable platform for identifying and verifying the genetic basis and molecular mechanisms of DIC.

2016-04-18 | GSE76314 | 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

The Cardiac Endothelial Cell cGAS-STING Pathway Promotes Doxorubicin-Induced Cardiotoxicity via CD38-Mediated NAD Decline and Mitochondrial Dysfunction

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-03-02 | GSE226116 | GEO

Targets of miR-212/132 in doxorubicin-induced cardiotoxicity

Project description:We overexpressed miR-212/132 by AAV9 in mouse model of doxorubicin-induced cardiotoxicity and wanted to identify myocardial targets of miR-212/132 in this model.

2018-12-29 | GSE121965 | GEO

Transcriptomic analysis of folic acid effects in doxorubicin-induced cardiotoxicity

Project description:Doxorubicin (DOXO), a chemotherapeutic drug, is cardiotoxic. We hypothesized that folic acid is an effective therapeutic agent in a mouse model of DOXO-induced cardiotoxicity. We performed genome-wide expression profiling to identify the underlying mechanisms. Male C57Bl6 2-mo old mice received DOXO (1x20 mg/kg, ip) or saline (sham). FA (10 mg/d) or placebo (plac) was administered 7d before DOXO administration until the end of the experiment (10d).

2015-11-12 | E-GEOD-64476 | biostudies-arrayexpress

Transcriptomic analysis of folic acid effects in doxorubicin-induced cardiotoxicity

2015-11-12 | GSE64476 | GEO

Transcriptional analysis of doxorubicin-induced cardiotoxicity

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

Analysis of potential transcriptomic biomarkers for doxorubicin cardiotoxicity in peripheral blood

Project description:The aim of this study is the characterize and compare heart and PBMC transcriptomes of rats treated with doxorubicin in order to isolate a list of similarly differentially regulated genes with an ultimate goal to indentify PBMC biomarkers for early prediction of doxirubicinduced cardiotoxicity Total RNA was isolated from PBMC and hearts of rats treated with doxirubicin or saline for 48 hrs and used for gene expression

2013-12-31 | E-GEOD-37260 | biostudies-arrayexpress

Analysis of potential transcriptomic biomarkers for doxorubicin cardiotoxicity in peripheral blood

2013-12-31 | GSE37260 | GEO

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