In vivo and in vitro protective effects of shengmai injection against doxorubicin-induced cardiotoxicity

• Published in: Pharmaceutical biology Vol. 60; no. 1; pp. 638 - 651
• Main Authors: Zhou, Peng, Gao, Ge, Zhao, Chun-chun, Li, Jing-ya, Peng, Jian-fei, Wang, Shu-shu, Song, Rui, Shi, Hui, Wang, Liang
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 31.12.2022; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Biological Sciences; Cardiomyocytes; Cardiomyopathy; Cardiotoxicity; Cardiotoxicity - prevention & control; Cells, Cultured; Congestive heart failure; Creatine; Creatine kinase; DNA nucleotidylexotransferase; DOX; Doxorubicin; Doxorubicin - toxicity; Drug Combinations; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - pharmacology; heart failure; Heme oxygenase (decyclizing); histology; Kelch-Like ECH-Associated Protein 1 - chemistry; Kelch-Like ECH-Associated Protein 1 - physiology; Kinases; L-Lactate dehydrogenase; Labeling; lactate dehydrogenase; Lactic acid; malondialdehyde; Molecular Docking Simulation; Molecular modelling; mRNA; Myocardium - pathology; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - physiology; Nrf2/Keap1 signal pathway; oxidative; Oxygenase; Protein expression; Protein folding; protein synthesis; Proteins; Rats; Rats, Sprague-Dawley; Razoxane; Signal transduction; Signal Transduction - drug effects; Superoxide dismutase; Western blotting; oxidative; apoptosis; DOX; Nrf2/Keap1 signal pathway
• ISSN: 1388-0209; 1744-5116; 1744-5116
• DOI: 10.1080/13880209.2022.2046801

Shengmai injection (SMI) has been used to treat heart failure. This study determines the molecular mechanisms of SMI against cardiotoxicity caused by doxorubicin (DOX). In vivo, DOX (15 mg/kg) was intraperitoneally injected in model, Dex (dexrazoxane), SMI-L (2.7 mL/kg), SMI-M (5.4 mL/kg), and SMI-H (10.8 mL/kg) for 7 consecutive days. Hematoxylin-eosin (HE) and Masson staining were used to evaluate histological changes, and cardiomyocyte apoptosis was identified using TdT-mediated dUTP nick-end labelling (TUNEL). Enzymatic indexes were determined. mRNA and protein expressions were analysed through RT-qPCR and Western blotting. In vitro, H9c2 cells were divided into control group, model group (2 mL 1 μM DOX), SMI group, ML385 group, and SMI + ML385 group, the intervention lasted for 24 h. mRNA and protein expressions were analysed. SMI markedly improved cardiac pathology, decreased cardiomyocyte apoptosis, increased creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), decreased superoxide dismutase (SOD). Compared with the model group, the protein expression of nuclear factor erythroid2-related factor 2 (Nrf2) (SMI-L: 2.42-fold, SMI-M: 2.67-fold, SMI-H: 3.07-fold) and haem oxygenase-1(HO-1) (SMI-L: 1.64-fold, SMI-M: 2.01-fold, SMI-H: 2.19-fold) was increased and the protein expression of kelch-like ECH-associated protein 1 (Keap1) (SMI-L: 0.90-fold, SMI-M: 0.77-fold, SMI-H: 0.66-fold) was decreased in SMI groups and Dex group in vivo. Additionally, SMI dramatically inhibited apoptosis, decreased CK, LDH and MDA levels, and enhanced SOD activity. Our results demonstrated that SMI reduced DOX-induced cardiotoxicity via activation of the Nrf2/Keap1 signalling pathway. This study revealed a new mechanism by which SMI alleviates DOX-induced 45 cardiomyopathy by modulating the Nrf2/Keap1 signal pathway.