Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Rats

Author:

Pereira Gonçalo C12ORCID,Pereira Susana P13ORCID,Pereira Francisco B45ORCID,Lourenço Nuno4ORCID,Lumini José A678ORCID,Pereira Claudia V19ORCID,Bjork James A10,Magalhães José6ORCID,Ascensão António6ORCID,Wieckowski Mariusz R11ORCID,Moreno António J112ORCID,Wallace Kendall B10,Oliveira Paulo J1ORCID

Affiliation:

1. CNC – Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech, Cantanhede, Portugal

2. School of Biochemistry, University Walk, University of Bristol, Bristol, UK

3. Research Centre in Physical Activity Health and Leisure (CIAFEL), Faculty of Sports, University of Porto, Porto, Portugal

4. Centre for Informatics and Systems, University of Coimbra, Polo II, Pinhal de Marrocos, Coimbra, Portugal

5. Coimbra Polytechnic – ISEC, Coimbra, Portugal

6. Health and Leisure, Faculty of Sport Sciences, University of Porto, Research Centre in Physical Activity, Porto, Portugal

7. Faculty of Health Sciences, University of Fernando Pessoa, Porto, Portugal

8. LABIOMEP – Porto Biomechanics Laboratory, Porto University, Porto, Portugal

9. University of Miami Miller School of Medicine, Neurological Research Building, Miami, Florida

10. Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, Minnesota

11. Nencki Institute of Experimental Biology, Warsaw, Poland

12. Department of Life Sciences, University of Coimbra, Coimbra, Portugal

Abstract

Abstract Doxorubicin (DOX) is an anticancer drug widely used to treat human and nonhuman tumors but the late and persistent cardio-toxicity reduces the therapeutic utility of the drug. The full mechanism(s) of DOX-induced acute, subchronic and delayed toxicity, which has a preponderant mitochondrial component, remains unclear; therefore, it is clinically relevant to identify early markers to identify patients who are predisposed to DOX-related cardiovascular toxicity. To address this, Wistar rats (16 weeks old) were treated with a single DOX dose (20 mg/kg, i.p.); then, mRNA, protein levels and functional analysis of mitochondrial endpoints were assessed 24 h later in the heart, liver, and kidney. Using an exploratory data analysis, we observed cardiac-specific alterations after DOX treatment for mitochondrial complexes III, IV, and preferentially for complex I. Conversely, the same analysis revealed complex II alterations are associated with DOX response in the liver and kidney. Interestingly, H2O2 production by the mitochondrial respiratory chain as well as loss of calcium-loading capacity, markers of subchronic toxicity, were not reliable indicators of acute DOX cardiotoxicity in this animal model. By using sequential principal component analysis and feature correlation analysis, we demonstrated for the first time alterations in sets of transcripts and proteins, but not functional measurements, that might serve as potential early acute markers of cardiac-specific mitochondrial toxicity, contributing to explain the trajectory of DOX cardiac toxicity and to develop novel interventions to minimize DOX cardiac liabilities.

Funder

Foundation for Science and Technology

FCT

Publisher

Oxford University Press (OUP)

Subject

Toxicology

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