Proanthocyanidin alleviates doxorubicin-induced cardiac injury by inhibiting NF-kB pathway and modulating oxidative stress, cell cycle, and fibrogenesis

Kadry M Sadek; Sahar F E Mahmoud; Mohamed F Zeweil; Tarek K Abouzed

doi:10.1002/jbt.22716

Proanthocyanidin alleviates doxorubicin-induced cardiac injury by inhibiting NF-kB pathway and modulating oxidative stress, cell cycle, and fibrogenesis

J Biochem Mol Toxicol. 2021 Apr;35(4):e22716. doi: 10.1002/jbt.22716. Epub 2021 Jan 23.

Authors

Kadry M Sadek¹, Sahar F E Mahmoud², Mohamed F Zeweil¹, Tarek K Abouzed³

Affiliations

¹ Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
² Department of Histology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
³ Department of Biochemistry, Faculty of Veterinary Medicine, Kafr El-Sheikh University, Damanhour, Egypt.

PMID: 33484087
DOI: 10.1002/jbt.22716

Abstract

This study investigated the potential mechanism(s) and the signaling pathway(s) underlying the prophylactic effect of proanthocyanidin extract (PE) against doxorubicin (DOX)-induced cardiotoxicity in rats. A total of 32 male albino rats were randomly allocated into four groups. Control rats were orally administrated normal saline. Rats in the second group were orally administrated PE (50 mg/kg bw/once daily) for 4 weeks. Rats in the third group were intraperitoneally injected with DOX (10 mg/kg on Days 3, 9, 15, and 21 of the experiment). Rats in the fourth group were injected with DOX and PE simultaneously for 4 weeks. DOX significantly augmented the levels of serum heart damage biomarkers. In addition, histopathology indicated that DOX-induced cardiac tissue injury upregulated the expression of fibrogenic factors, alpha smooth muscle actin (α-SMA), transforming growth factor β1 (TGF- β1), and p16^INK4A . Downregulation of cell proliferation markers, cyclin-dependent kinase-4 (CDK4), and retinoblastoma (Rb) was also observed. Furthermore, DOX-induced oxidative and inflammatory stress resulted in increased cardiac malondialdehyde (MDA), protein carbonyl (PC), interleukin-2 (IL-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Decreased cardiac glutathione (GSH) levels and enzyme activity of catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) were observed. Treatment of DOX-induced rat cardiotoxicity with PE normalized serum parameters for the aforementioned parameters and alleviated cardiac tissue structure. Furthermore, reduced cardiac tissue α-SMA and TGF-β1, and increased CDK4 and Rb protein expression, along with the amelioration of oxidative and inflammatory effects were observed. PE attenuates DOX-induced cardiomyocyte inflammation possibly by attenuating the nuclear factor kappa-B (NF- kB) signaling pathway. These results indicate that PE may be useful as a preventative agent against DOX-induced cardiac toxicity.

Keywords: cardiac damage; cyclin-dependent kinases; doxorubicin; fibrogenesis; proanthocyanidins; retinoblastoma.

MeSH terms

Animals
Cell Cycle / drug effects*
Doxorubicin / adverse effects*
Doxorubicin / pharmacology
Fibrosis
Gene Expression Regulation / drug effects
Heart Injuries* / chemically induced
Heart Injuries* / drug therapy
Heart Injuries* / metabolism
Male
Muscle Proteins / biosynthesis
Myocardium / metabolism
NF-kappa B / metabolism*
Oxidative Stress / drug effects*
Proanthocyanidins / pharmacology*
Rats
Signal Transduction / drug effects*

Substances

Muscle Proteins
NF-kappa B
Proanthocyanidins
proanthocyanidin
Doxorubicin