Irigenin treatment alleviates doxorubicin (DOX)-induced cardiotoxicity by suppressing apoptosis, inflammation and oxidative stress via the increase of miR-425.

Abstract

Doxorubicin (DOX) is an eff ;ective chemotherapeutic drug to suppress the progression of various types of tumors. However, its clinical application has been largely limited due to its potential cardiotoxicity. MicroRNAs (miRNAs) are emerged as critical regulators of cardiac injury. This study was aimed to explore the effects of irigenin (IR), as an isoflavonoid isolated from the rhizome of Belamcanda chinensis, on DOX-induced cardiotoxicity using the in vivo and in vitrostudies. The results indicated that DOX-induced fibrosis, cardiac dysfunction and injury were markedly attenuated by IR through reducing apoptosis, oxidative stress and inflammation in heart tissue samples. Importantly, DOX resulted in a remarkable decrease of miR-425 in heart tissues and cells, which was significantly rescued by IR. Receptor-interacting protein kinase 1 (RIPK1) was discovered to be a direct target of miR-425. DOX induced over-expression of RIPK1 both in vivo and in vitro, which were greatly decreased by IR. Transfection with miR-425 mimic could inhibit RIPK1 expression, whereas reducing miR-425 increased RIPK1 expression levels. In parallel to miR-425 over-expression, RIPK1 knockdown could attenuate apoptosis, reactive oxygen species (ROS) production and inflammation in HL-1 cells. However, over-expression of RIPK1 markedly abolished miR-425 mimic-induced apoptosis, ROS accumulation and inflammatory response in DOX-exposed cells. Herein, miR-425 could ameliorate cardiomyocyte injury through directly targeting RIPK1. Furthermore, activation of miR-425 by IR markedly improved DOX-induced cardiotoxicity, and therefore IR could be considered as a promising therapeutic agent for the treatment of cardiac injury.

• Authors: Langtao Guo, Xueping Zheng, Enwei Wang, Xusheng Jia, Gang Wang, Jian Wen
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 125 Pg. 109784 (May 2020) ISSN: 1950-6007 [Electronic] France
• PMID: 32092815 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier Masson SAS.

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Cytokines
• Isoflavones
• MIRN425 microRNA, mouse
• MicroRNAs
• irigenin
• Doxorubicin

Topics

• Animals
• Antineoplastic Agents (adverse effects)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Cardiotoxicity (prevention & control)
• Cytokines (metabolism)
• Doxorubicin (adverse effects, pharmacology)
• Inflammation (metabolism)
• Isoflavones (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• MicroRNAs (metabolism)
• Myocytes, Cardiac (drug effects)
• Oxidative Stress (drug effects)