IMR Press / FBL / Volume 28 / Issue 3 / DOI: 10.31083/j.fbl2803045
Open Access Original Research
Astragaloside IV Inhibits NLRP3 Inflammasome-Mediated Pyroptosis via Activation of Nrf-2/HO-1 Signaling Pathway and Protects against Doxorubicin-Induced Cardiac Dysfunction
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1 Affiliated Hospital of Jining Medical University, Clinical Medical College, Jining Medical University, 272000 Jining, Shandong, China
2 Jining Key Laboratory for Diagnosis and Treatment of Cardiovascular Diseases, 272000 Jining, Shandong, China
3 Cheeloo College of Medicine, Shandong University, 250012 Jinan, Shandong, China
*Correspondence: (Jinguo Zhang); (Cheng Shen)
Front. Biosci. (Landmark Ed) 2023, 28(3), 45;
Submitted: 19 October 2022 | Revised: 13 December 2022 | Accepted: 14 December 2022 | Published: 3 March 2023
Copyright: © 2023 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: Doxorubicin (DOX) is an effective broad-spectrum antitumor drug, but its clinical application is limited due to the side effects of cardiac damage. Astragaloside IV (AS-IV) is a significant active component of Astragalus membranaceus that exerts cardioprotective effects through various pathways. However, whether AS-IV exerts protective effects against DOX-induced myocardial injury by regulating the pyroptosis is still unknown and is investigated in this study. Methods: The myocardial injury model was constructed by intraperitoneal injection of DOX, and AS-IV was administered via oral gavage to explore its specific protective mechanism. Cardiac function and cardiac injury indicators, including lactate dehydrogenase (LDH), cardiac troponin I (cTnI), creatine kinase isoenzyme (CK-MB), and brain natriuretic peptide (BNP), and histopathology of the cardiomyocytes were assessed 4 weeks post DOX challenge. Serum levels of IL-1β, IL-18, superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) and the expression of pyroptosis and signaling proteins were also determined. Results: Cardiac dysfunction was observed after the DOX challenge, as evidenced by reduced ejection fraction, increased myocardial fibrosis, and increased BNP, LDH, cTnI, and CK-MB levels (p < 0.05, N = 3–10). AS-IV attenuated DOX-induced myocardial injury. The mitochondrial morphology and structure were also significantly damaged after DOX treatment, and these changes were restored after AS-IV treatment. DOX induced an increase in the serum levels of IL-1β, IL-18, SOD, MDA and GSH as well as an increase in the expression of pyroptosis-related proteins (p < 0.05, N = 3–6). Besides, AS-IV depressed myocardial inflammatory-related pyroptosis via activation of the expressions of nuclear factor E2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) (p < 0.05, N = 3). Conclusions: Our results showed that AS-IV had a significant protective effect against DOX-induced myocardial injury, which may be associated with the activation of Nrf-2/HO-1 to inhibit pyroptosis.

Astragalus membranaceus
cardiac dysfunction
2019WS364/Shandong Province Medical and health Science and Technology Development Program
82000269/National Nature Science Foundation of China
2018SMNS006/Jining City Science and Technology Key Research and Development Program
JYHL2018FMS02/Research Fund for Academician Lin He New Medicine
2021YXNS069/Jining City Science and Technology Key Research and Development Program
Fig. 1.
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