Juvenile exposure to doxorubicin alters the cardiovascular response to adult-onset psychosocial stress in mice

Abstract

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.

Keywords:

• Doxorubicin
• cardiotoxicity
• psychosocial stress
• childhood cancer
• survivorship

Acknowledgments

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.

Disclosure statement

The authors declare that they do not have any financial or non-financial conflicts of interest concerning this manuscript.

Data availability statement

The data that support the findings of this study are available in the methods and/or supplementary material of this article.

Additional information

Funding

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.

Notes on contributors

Marianne K. O. Grant

Marianne K.O. Grant, BA is a Senior Researcher in the Zordoky lab, University of Minnesota College of Pharmacy. Her current work focuses on cancer therapy-induced cardiovascular complications.

Maria Razzoli

Maria Razzoli, PhD is a Senior Scientist in the Bartolomucci lab and the behavioral/metabolic specialist of the Physiology Core of the University of Minnesota Medical School. Her current work focuses on rodent stress models and induced behavioral and physiological alterations, including stress accelerated aging phenotypes.

Ibrahim Y. Abdelgawad

Ibrahim Y. Abdelgawad, BSc is a PhD Candidate in the Zordoky lab, University of Minnesota College of Pharmacy. His current work focuses on cancer therapy-induced senescence.

Rachel Mansk

Rachel Mansk, BA is a Research Scientist in the Bartolomucci lab and a graduate student at the University of Minnesota School of Public Health. Rachel's research focuses on the social determinants of health.

Davis Seelig

Davis Seelig, DVM, PhD is Associate Professor, Department of Veterinary Clinical Sciences, University of Minnesota College of Veterinary Medicine and Director of the Comparative Pathology Shared Resource at the University of Minnesota Masonic Cancer Center. His research focuses on comparative and experimental pathology.

Alessandro Bartolomucci

Alessandro Bartolomucci, PhD is Professor, Ancel Keys Biomedical Scholar in Physiology and Metabolism, and Director of the Physiology Core at the Department of Integrative Biology and Physiology, University of Minnesota Medical School. His laboratory is primarily interested in metabolic physiology, stress physiology and social determinants of health and aging.

Beshay N. Zordoky

Beshay N. Zordoky, PhD is Associate Professor of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy. His current research interests include cancer therapy-induced cardiovascular complications and therapy-induced senescence.