Childhood cancer survivors have a high risk for premature cardiovascular diseases, mainly due to cardiotoxic cancer treatments such as doxorubicin (DOX). Psychosocial stress is a significant cardiovascular risk factor and an enormous burden in childhood cancer survivors. Although observational studies suggest that psychosocial stress is associated with cardiovascular complications in cancer survivors, there is no translationally relevant animal model to study this interaction. We established a “two-hit” model in which juvenile mice were administered DOX (4 mg/kg/week for 3 weeks), paired to a validated model of chronic subordination stress (CSS) 5 weeks later upon reaching adulthood. Blood pressure, heart rate, and activity were monitored by radio-telemetry. At the end of CSS experiment, cardiac function was assessed by echocardiography. Cardiac fibrosis and inflammation were assessed by histopathologic analysis. Gene expressions of inflammatory and fibrotic markers were determined by PCR. Juvenile exposure to DOX followed by adult-onset CSS caused cardiac fibrosis and inflammation as evident by histopathologic findings and upregulated gene expression of multiple inflammatory and fibrotic markers. Intriguingly, juvenile exposure to DOX blunted CSS-induced hypertension but not CSS-induced tachycardia. There were no significant differences in cardiac function parameters among all groups, but juvenile exposure to DOX abrogated the hypertrophic response to CSS. In conclusion, we established a translationally relevant mouse model of juvenile DOX-induced cardiotoxicity that predisposes to adult-onset stress-induced adverse cardiac remodeling. Psychosocial stress should be taken into consideration in cardiovascular risk stratification of DOX-treated childhood cancer survivors.
Bibliographical noteFunding Information:
This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL151740 (B.N.Z. and A.B.), the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494 (B.N.Z.), the American Cancer Society Institutional Research Grant #CON000000061006 (B.N.Z), and the Minnesota Partnership for Biotechnology and Medical Genomics #18.04 (A.B.). I.Y.A. is supported by the Bighley Graduate Fellowship from the College of Pharmacy, University of Minnesota. Experiments using the NanoDrop 8000 and ABI 7900 HT were done with staff support at the University of Minnesota Genomics Center. Experiments using the Vevo 2100 echocardiography system were done with staff support at the University of Minnesota Imaging Center. Processing of heart tissues for histopathological analysis was performed with staff support at the Comparative Pathology Shared Resource, University of Minnesota Masonic Cancer Center. The stress and radiotelemetry experiments were conducted at the Physiology Core, University of Minnesota. We would like to thank Pilar Ariza for performing the surgeries, and Jan Pierre Pallais for help with the social stress experiments.
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
- childhood cancer
- psychosocial stress
PubMed: MeSH publication types
- Journal Article
- Observational Study
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't