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Irbesartan suppresses cardiac toxicity induced by doxorubicin via regulating the p38-MAPK/NF-κB and TGF-β1 pathways

  • Nermin T. El-Said
  • Eman A. MohamedEmail author
  • Ragia A. Taha
Original Article
  • 11 Downloads

Abstract

Doxorubicin (DOX) so far continues to be one of the most potent and effective anticancer drugs. Therefore, it is still needed to search for a safe and effective therapy that can opposite DOX-induced cardiotoxicity. Irbesartan (IRB), an angiotensin II receptor blocker, has a wide-ranging variety of biological activities. The present study was designed to explore the possible protective effects of IRB against DOX-induced cardiotoxicity and the underlying mechanisms. Rats were divided into four groups: control, IRB (40 mg/kg, orally/daily) for 3 weeks, DOX (2.5 mg/kg, intraperitoneally/ three times weekly) for 2 weeks to obtain cumulative dose of 15 mg/kg, and finally IRB + DOX group. IRB inhibited cardiotoxicity induced by DOX which was evident by ECG changes, alterations of cardiac enzymes and histopathological changes. IRB improved DOX-induced alterations in oxidative/nitrosative status by decreasing lipid peroxidation and nitric oxide (NO) content in addition to increasing the antioxidant capacity. In addition, DOX triggers the cardiac expression of tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB) where IRB diminished DOX-induced alterations in theses parameters. Moreover, DOX significantly increase the expression levels of caspase-3 and transforming growth factor-beta 1 (TGF-β1), while IRB exhibited anti-apoptotic and anti-fibrotic effects where it abolished these elevations. Meanwhile, DOX-induced activation of p38-mitogen activated protein kinase (p38-MAPK) which was inhibited by IRB. Collectively, these results proposed that IRB afforded a significant protection against DOX-induced cardiac damage by means of antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic remodeling mechanisms. These mechanisms are possibly mediated, at least in part, by alterations of TGF-β1/p38-MAPK/NF-κB signaling.

Keywords

Cardiotoxicity Doxorubicin Irbesartan Nuclear factor kappa B (NF-κB) Transforming growth factor-beta 1 (TGF-β1) p38-Mitogen-activated protein kinase (p38-MAPK) 

Abbreviations

Ang-II

Angiotensin II

ARBs

Angiotensin receptor blockers

AT1R

Angiotensin II type 1 receptor

CK-MB

Creatine kinase MB

cTn-I

Serum cardiac troponin-I

CVD

Cardiovascular diseases

DOX

Doxorubicin

ECG

Electrocardiography

ELISA

Enzyme-linked immunosorbent assay

GSH

Reduced glutathione

H&E

Hematoxylin and eosin

I/R

Ischemia reperfusion

iNOS

Inducible NO synthase

IRB

Irbesartan

MDA

Malondialdehyde

NF-κB

Nuclear factor kappa B

NO

Nitric oxide

p38-MAPK

p38-Mitogen-activated protein kinase

PPAR-γ

Peroxisome proliferator-activated receptor gamma

RAS

Renin-angiotensin system

RHW

Relative heart weight

ROS

Reactive oxygen species

TAC

Total antioxidant capacity

TBARS

Thiobarbituric acid reactive substances

TGF-β1

Transforming growth factor-beta 1

TNF-α

Tumor necrosis factor-α

Notes

Author contributions

RA developed the research idea, performed and supervised the experiment execution and the data analysis, and revised the manuscript. EM designed the research idea and the experiments, performed and supervised the experiment execution, and wrote and revised the manuscript. NT performed the experiments, collected the data, and performed the graphical and statistical analysis.

Compliance with ethical standards

The study complies with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publications No. 8023, revised 1978) and is approved by the Ethics Committee of Faculty of Pharmacy, Al-Azhar University.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls)Al-Azhar UniversityCairoEgypt

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