Fumarate attenuated doxorubicin-induced cardiac injury through modulation of endothelial nitric oxide synthase expression and transforming growth factor-β1 signalling

Osaze Edosuyi; Eghosa B. Osagiede; Nosakhare Eguasa; Samuel O. Ayodele; Eze A. Eunice; Elaigwu R. Ojonugba; Vashti Edosuyi; Olusola O. Elekofehinti; Aladuna J. Omo-Erhabor; Ighodaro Igbe

doi:10.56782/pps.677

Published : 2025-12-11

No. 2025 (Early Access)

Fumarate attenuated doxorubicin-induced cardiac injury through modulation of endothelial nitric oxide synthase expression and transforming growth factor-β1 signalling

Osaze Edosuyi

Eghosa B. Osagiede

Nosakhare Eguasa

Samuel O. Ayodele

Eze A. Eunice

Elaigwu R. Ojonugba

Vashti Edosuyi

Olusola O. Elekofehinti

Aladuna J. Omo-Erhabor

Ighodaro Igbe

DOI: https://doi.org/10.56782/pps.677

Abstract

Doxorubicin (dox) is an anticancer agent with adverse effects, such as cardiac injury. Fumarate, a tricarboxylic acid cycle metabolite, has been shown to ameliorate cardiac injury. This study investigated the possible cardioprotective action of fumarate in dox-induced cardiac injury. Male Wistar rats were divided into four groups (n=8); control (distilled water 10 ml/kg, po), dox (10 mg/kg, ip), dox (10 mg/kg, ip) + fumarate (50 mg/kg, po) and dox (10 mg/kg, ip) + fumarate (100 mg/kg, po). The animals were treated for 10 days and euthanized. Blood was withdrawn, the heart was excised and immediately frozen for biochemical and molecular analyses. Fumarate reduced serum levels of troponin-T (57.5 %, p<0.05) at 50 mg/kg and (55 % p<0.05) at 100 mg/kg in the dox group. Malondialdehyde formation was reduced from 69.6±3.6 mmol/mg in the dox group to 52.4±3.4 nmol MDA/mg protein at 50 mg/kg and 39.4±0.9 nmol MDA/mg protein at 100 mg/kg in fumarate-treated dox rats (p<0.001). Similarly, catalase (CAT) (9-fold), superoxide dismutase (SOD) (3-fold), and glutathione peroxidase (GPx) (3-fold) activity, which was significantly decreased in the dox group, was reversed by fumarate at 100 mg/kg. Transforming growth factor (TGF) β1 expression was reduced by fumarate (p<0.001). The expression of endothelial nitric oxide synthase (eNOS) was reduced with the administration of fumarate at 100 mg/kg (26.2±1.6, p<0.001) in dox-treated rats. The data have shown that fumarate ameliorated the dox-induced cardiomyopathy by increasing CAT, SOD, and GPx activities and a reduction in TGFβ1 and eNOS expression.

Keywords:

Cardiac injury, doxorubicin, fumarate, endothelial nitric oxide synthase, transforming growth factorβ1, troponin

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Edosuyi, O., Osagiede, E. B., Eguasa, N., Ayodele, S. O., Eunice, E. A., Ojonugba, E. R., … Igbe, I. (2025). Fumarate attenuated doxorubicin-induced cardiac injury through modulation of endothelial nitric oxide synthase expression and transforming growth factor-β1 signalling. Prospects in Pharmaceutical Sciences, (2025 (Early Access). https://doi.org/10.56782/pps.677

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Osaze Edosuyi

osaze.edosuyi@uniben.edu

Affiliation:

Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Benin PMB 1154, Benin City, Nigeria Nigeria

Eghosa B. Osagiede

Affiliation:

Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Benin PMB 1154, Benin City, Nigeria Nigeria

Nosakhare Eguasa

Affiliation:

Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Benin PMB 1154, Benin City, Nigeria Nigeria

Samuel O. Ayodele

Affiliation:

Department of Medical Laboratory Science, School of Basic Medical Sciences, College of Medical Sciences, University of Benin, Nigeria Nigeria

Eze A. Eunice

Affiliation:

Department of Medical Laboratory Science, School of Basic Medical Sciences, College of Medical Sciences, University of Benin, Nigeria Nigeria

Elaigwu R. Ojonugba

Affiliation:

Department of Medical Laboratory Science, School of Basic Medical Sciences, College of Medical Sciences, University of Benin, Nigeria Nigeria

Vashti Edosuyi

Affiliation:

Department of Child Health, University of Benin Teaching Hospital, Benin City, Nigeria Nigeria

Olusola O. Elekofehinti

Affiliation:

Bioinformatics and Molecular Biology Laboratory. Department of Biochemistry, Federal University of Technology Akure, Nigeria Nigeria

Aladuna J. Omo-Erhabor

Affiliation:

Department of Medical Laboratory Science, School of Basic Medical Sciences, College of Medical Sciences, University of Benin, Nigeria Nigeria

Ighodaro Igbe

Affiliation:

Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Benin PMB 1154, Benin City, Nigeria Nigeria