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- Title
Characterization of systolic and diastolic function, alongside proteomic profiling, in doxorubicin-induced cardiovascular toxicity in mice.
- Authors
Krüger, Dustin N.; Bosman, Matthias; Van Assche, Charles X.L.; Wesley, Callan D.; Cillero-Pastor, Berta; Delrue, Leen; Heggermont, Ward; Bartunek, Jozef; De Meyer, Guido R. Y.; Van Craenenbroeck, Emeline M.; Guns, Pieter-Jan; Franssen, Constantijn
- Abstract
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.
- Subjects
PROTEIN analysis; LEFT heart ventricle; CARDIOMYOPATHIES; LIQUID chromatography-mass spectrometry; VENTRICULAR ejection fraction; RESEARCH funding; GENETIC markers; PULMONARY edema; CELL physiology; HEART physiology; HEART failure; HEART; MANN Whitney U Test; MICE; VENTRICULAR dysfunction; GENE expression; IMMUNOHISTOCHEMISTRY; DIASTOLIC blood pressure; PROTEOMICS; DOXORUBICIN; CARDIOTOXICITY; ANIMAL experimentation; CARDIOVASCULAR system physiology; WESTERN immunoblotting; ENDOTHELIAL cells; ANESTHETICS; ANALYSIS of variance; SYSTOLIC blood pressure; DATA analysis software; HEART ventricles; ECHOCARDIOGRAPHY; TIME; RELAXATION for health; HISTOLOGY
- Publication
Cardio-Oncology, 2024, Vol 10, Issue 1, p1
- ISSN
2057-3804
- Publication type
Article
- DOI
10.1186/s40959-024-00241-1