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Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice

Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with breast cancer could identify new mechanisms of anthracycline cardiac toxicity. We measured changes in 1317 proteins in anthracycli...

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Detalles Bibliográficos
Autores principales: Liu, Jing, Lane, Sarah, Lall, Rahul, Russo, Michele, Farrell, Laurie, Debreli Coskun, Melis, Curtin, Casie, Araujo-Gutierrez, Raquel, Scherrer-Crosbie, Marielle, Trachtenberg, Barry H., Kim, Jonghan, Tolosano, Emanuela, Ghigo, Alessandra, Gerszten, Robert E., Asnani, Aarti
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9788780/
https://www.ncbi.nlm.nih.gov/pubmed/36563141
http://dx.doi.org/10.1126/sciadv.adc9245
Descripción
Sumario:Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with breast cancer could identify new mechanisms of anthracycline cardiac toxicity. We measured changes in 1317 proteins in anthracycline-treated patients (n = 30) and replicated key findings in a second cohort (n = 31). An increase in the heme-binding protein hemopexin (Hpx) 3 months after anthracycline initiation was associated with cardiac toxicity by echocardiography. To assess the functional role of Hpx, we administered Hpx to wild-type (WT) mice treated with Dox and observed improved cardiac function. Conversely, Hpx(−/−) mice demonstrated increased Dox cardiac toxicity compared to WT mice. Initial mechanistic studies indicate that Hpx is likely transported to the heart by circulating monocytes/macrophages and that Hpx may mitigate Dox-induced ferroptosis to confer cardioprotection. Together, these observations suggest that Hpx induction represents a compensatory response during Dox treatment.