IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity
Abstract Doxorubicin (DOX) is a first-line chemotherapy agent known for its cardiac toxicity. DOX-induced cardiotoxicity (DIC) severely limits the use for treating malignant tumors and is associated with a poor prognosis. The sensitivity to DIC varies among patients, but the precise mechanisms remai...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01389-7 |
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| author | Haoyu Ji Wenya Ma Xu Liu Hongyang Chen Yining Liu Zhongyu Ren Daohong Yin Ao Cai Zizhen Zhang Xin Wang Wei Huang Leping Shi Yanan Tian Yang Yu Xiuxiu Wang Yang Li Yu Liu Benzhi Cai |
| author_facet | Haoyu Ji Wenya Ma Xu Liu Hongyang Chen Yining Liu Zhongyu Ren Daohong Yin Ao Cai Zizhen Zhang Xin Wang Wei Huang Leping Shi Yanan Tian Yang Yu Xiuxiu Wang Yang Li Yu Liu Benzhi Cai |
| author_sort | Haoyu Ji |
| collection | DOAJ |
| description | Abstract Doxorubicin (DOX) is a first-line chemotherapy agent known for its cardiac toxicity. DOX-induced cardiotoxicity (DIC) severely limits the use for treating malignant tumors and is associated with a poor prognosis. The sensitivity to DIC varies among patients, but the precise mechanisms remain elusive. Here we constructed a mouse model of DIC using DOX to investigate potential mechanisms contributing to the differential susceptibility to DIC. Through surface-enhanced Raman spectroscopy and single-cell RNA sequencing, we explored the mechanisms underlying DIC phenotypic variations. In vitro and in vivo studies with small-molecule drugs were conducted. DIC-insensitive mice displayed preserved ejection fractions, lower DOX levels in cardiac tissues and higher levels in the serum. Single-cell RNA sequencing revealed differences of gene expression in cardiac endothelial cells between DIC-insensitive and DIC-sensitive groups. The expression of IFN-γ pathway-related genes was high in DIC-insensitive mice. IFN-γ administration decreased the DOX distribution in cardiac tissues, whereas PPAR-γ activation increased DIC susceptibility. IFN-γ stimulation upregulated P-glycoprotein expression, leading to increased DOX efflux and DIC insensitivity. Our model provides insights into the mechanisms of DIC sensitivity and potential preventive strategies. |
| format | Article |
| id | doaj-art-1aaa9fa1a9ad48d6a924e7418f04888b |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-1aaa9fa1a9ad48d6a924e7418f04888b2025-02-09T12:14:12ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-01-0157124926310.1038/s12276-024-01389-7IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicityHaoyu Ji0Wenya Ma1Xu Liu2Hongyang Chen3Yining Liu4Zhongyu Ren5Daohong Yin6Ao Cai7Zizhen Zhang8Xin Wang9Wei Huang10Leping Shi11Yanan Tian12Yang Yu13Xiuxiu Wang14Yang Li15Yu Liu16Benzhi Cai17Department of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Laboratory Medicine at The Fourth Affiliated Hospital, Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Laboratory Medicine at The Fourth Affiliated Hospital, Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityResearch Unit of Health Sciences and Technology, Faculty of Medicine University of Oulu, Finland; Research Center for Innovative Technology of Pharmaceutical Analysis, College of Pharmacy, Harbin Medical UniversityDepartment of Laboratory Medicine at The Fourth Affiliated Hospital, Harbin Medical UniversityDepartment of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical UniversityAbstract Doxorubicin (DOX) is a first-line chemotherapy agent known for its cardiac toxicity. DOX-induced cardiotoxicity (DIC) severely limits the use for treating malignant tumors and is associated with a poor prognosis. The sensitivity to DIC varies among patients, but the precise mechanisms remain elusive. Here we constructed a mouse model of DIC using DOX to investigate potential mechanisms contributing to the differential susceptibility to DIC. Through surface-enhanced Raman spectroscopy and single-cell RNA sequencing, we explored the mechanisms underlying DIC phenotypic variations. In vitro and in vivo studies with small-molecule drugs were conducted. DIC-insensitive mice displayed preserved ejection fractions, lower DOX levels in cardiac tissues and higher levels in the serum. Single-cell RNA sequencing revealed differences of gene expression in cardiac endothelial cells between DIC-insensitive and DIC-sensitive groups. The expression of IFN-γ pathway-related genes was high in DIC-insensitive mice. IFN-γ administration decreased the DOX distribution in cardiac tissues, whereas PPAR-γ activation increased DIC susceptibility. IFN-γ stimulation upregulated P-glycoprotein expression, leading to increased DOX efflux and DIC insensitivity. Our model provides insights into the mechanisms of DIC sensitivity and potential preventive strategies.https://doi.org/10.1038/s12276-024-01389-7 |
| spellingShingle | Haoyu Ji Wenya Ma Xu Liu Hongyang Chen Yining Liu Zhongyu Ren Daohong Yin Ao Cai Zizhen Zhang Xin Wang Wei Huang Leping Shi Yanan Tian Yang Yu Xiuxiu Wang Yang Li Yu Liu Benzhi Cai IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity Experimental and Molecular Medicine |
| title | IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity |
| title_full | IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity |
| title_fullStr | IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity |
| title_full_unstemmed | IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity |
| title_short | IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity |
| title_sort | ifn γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin induced cardiotoxicity |
| url | https://doi.org/10.1038/s12276-024-01389-7 |
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