IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity

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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Main Authors: 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
Format: Article
Language:English
Published: Nature Publishing Group 2025-01-01
Series:Experimental and Molecular Medicine
Online Access:https://doi.org/10.1038/s12276-024-01389-7
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Summary: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.
ISSN:2092-6413

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