Yangxin granules alleviate doxorubicin-induced cardiotoxicity by suppressing oxidative stress and apoptosis mediated by AKT/GSK3β/β-catenin signaling

Abstract

Background Yangxin granules (YXC), a Chinese herbal medicine, have been confirmed to have clinical benefits in the treatment of heart failure. This study examined the effects and molecular mechanisms of YXC in the treatment of doxorubicin-induced cardiotoxicity in vitro. Methods H9c2 cardiomyocytes were pretreated with YXC (5, 10, or 20 mg/mL) or the AKT inhibitor MK-2206 (50 nM) before doxorubicin treatment (1 µM). Cell apoptosis, viability, inflammatory factor expression (TNF-α, IL-1β, and IL-6), and oxidative stress mediator levels including superoxide dismutase, reactive oxygen species, and malondialdehyde were detected. Results YXC increased the viability of H9c2 cells. In addition, doxorubicin inhibited AKT/GSK3β/β-catenin signaling, whereas YXC increased the expression of phosphorylated AKT and GSK3β, and β-catenin in doxorubicin-treated H9c2 cells. Moreover, T-cell factor/lymphoid enhancer factor signaling downstream of β-catenin was also activated by YXC. YXC pretreatment also inhibited doxorubicin-induced inflammation, oxidative stress, and apoptosis. However, MK-2206 reversed the effects of YXC in doxorubicin-treated H9c2 cells. Conclusions YXC alleviates doxorubicin-induced inflammation, oxidative stress, and apoptosis in H9c2 cells. These effects might be mediated by the AKT/GSK3β/β-catenin signaling pathway. YXC might have preventive effects against doxorubicin-induced heart failure.

Exploring the Mechanism of Danshensu in the Treatment of Doxorubicin-Induced Cardiotoxicity Based on Network Pharmacology and Experimental Evaluation

“…DOX-induced cardiotoxicity is classified as “heart failure disease” and “palpitation” in Chinese medicine ( 10 ) with palpitations and blood stasis as the main symptoms. Treatment should be based on activating blood stasis and warming the heart yang ( 11 ). Although dexrazoxane is the only drug approved by the FDA to protect against cardiotoxicity caused by anthracyclines, it still has side effects such as causing an increased incidence of second primary malignancies ( 12 ).…”

α-Cyperone Protects Cardiomyocytes against Oxygen-Glucose Deprivation-Induced Inflammation and Oxidative Stress by Akt/FOXO3a/NF-κB Pathway

“…Akt is a serine/threonine kinase that exerts an essential function in cell survival, cell growth, cell proliferation, angiogenesis, vasodilation, and cell metabolism [ 9 ]. According to reports, YXC attenuates DOX-induced apoptosis, oxidative stress, and inflammation in cardiomyocytes by motivating the Akt/GSK3 β / β -catenin signaling, whereas Akt inhibitors impede this effect of YXC [ 10 ]. Forkhead box O 3a (FOXO3a) is a critical transcription factor that is closely associated with various biological processes such as apoptosis, oxidative stress, autophagy, and inflammation [ 11 ].…”

Cardio-Oncology Preclinical Models: A Comprehensive Review

“…A cellular model using H9C2 cell line, demonstrated that yangxin granules -a Chinese herbal-had a protective effect against doxorubicin-induced heart failure (97). However, more experimental and clinical studies are warranted to investigate and confirm the cardioprotective action of yangxin.…”