Sex-related differences in delayed doxorubicin-induced cardiac dysfunction in C57BL/6 mice

Abdelgawad, Ibrahim Y.; George, Benu; Grant, Marianne K. O.; Huang, Yingbo; Shan, Yuting; Huang, R. Stephanie; Zordoky, Beshay N.

doi:10.1007/s00204-023-03678-y

Cited by 4 publications

(2 citation statements)

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“…Recently, Abdelgawad et al, applied proteomic profiling to investigate sex-related differences of cumulative 24 mg/kg DOX in C57BL/6N mice. In accordance with our results, they identified an increase of MHY7 as well as a reduction of immunoglobin heavy constant Mu (IGHM) in cardiac tissue of male mice [ 50 ]. Additionally, they reported upregulation of markers of cardiac damage such as myosin light chain 7 and natriuretic peptide A.…”

Section: Discussionsupporting

confidence: 90%

“…Serpina3 upregulation in the right ventricle of mice treated with DOX (cumulative dose 20 mg/kg) was previously reported as well [ 21 ]. In contrast, Abdelgawad, I. Y. et al, 2024, found that SERPINA3K was downregulated in the cardiac tissue of mice treated with cumulative 24 mg/kg of DOX but SERPINA3 was not reported [ 50 ]. The discrepancy between their study and the current work may relate to the use of a different strain, although this seems rather unlikely.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of systolic and diastolic function, alongside proteomic profiling, in doxorubicin-induced cardiovascular toxicity in mice

Krüger,

Bosman,

Van Assche

et al. 2024

Cardio-Oncology

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Background The anthracycline doxorubicin (DOX) is a highly effective anticancer agent, especially in breast cancer and lymphoma. However, DOX can cause cancer therapy-related cardiovascular toxicity (CTR-CVT) in patients during treatment and in survivors. Current diagnostic criteria for CTR-CVT focus mainly on left ventricular systolic dysfunction, but a certain level of damage is required before it can be detected. As diastolic dysfunction often precedes systolic dysfunction, the current study aimed to identify functional and molecular markers of DOX-induced CTR-CVT with a focus on diastolic dysfunction. Methods Male C57BL/6J mice were treated with saline or DOX (4 mg/kg, weekly i.p. injection) for 2 and 6 weeks (respectively cumulative dose of 8 and 24 mg/kg) (n = 8 per group at each time point). Cardiovascular function was longitudinally investigated using echocardiography and invasive left ventricular pressure measurements. Subsequently, at both timepoints, myocardial tissue was obtained for proteomics (liquid-chromatography with mass-spectrometry). A cohort of patients with CTR-CVT was used to complement the pre-clinical findings. Results DOX-induced a reduction in left ventricular ejection fraction from 72 ± 2% to 55 ± 1% after 2 weeks (cumulative 8 mg/kg DOX). Diastolic dysfunction was demonstrated as prolonged relaxation (increased tau) and heart failure was evident from pulmonary edema after 6 weeks (cumulative 24 mg/kg DOX). Myocardial proteomic analysis revealed an increased expression of 12 proteins at week 6, with notable upregulation of SERPINA3N in the DOX-treated animals. The human ortholog SERPINA3 has previously been suggested as a marker in CTR-CVT. Upregulation of SERPINA3N was confirmed by western blot, immunohistochemistry, and qPCR in murine hearts. Thereby, SERPINA3N was most abundant in the endothelial cells. In patients, circulating SERPINA3 was increased in plasma of CTR-CVT patients but not in cardiac biopsies. Conclusion We showed that mice develop heart failure with impaired systolic and diastolic function as result of DOX treatment. Additionally, we could identify increased SERPINA3 levels in the mice as well as patients with DOX-induced CVT and demonstrated expression of SERPINA3 in the heart itself, suggesting that SERPINA3 could serve as a novel biomarker.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%