Astragaloside IV Inhibits NLRP3 Inflammasome-Mediated Pyroptosis via Activation of Nrf-2/HO-1 Signaling Pathway and Protects against Doxorubicin-Induced Cardiac Dysfunction

Xueheng Chen; Chao Tian; Zhiqiang Zhang; Yiran Qin; Runqi Meng; Xuening Dai; Yuanyuan Zhong; Xiqing Wei; Jinguo Zhang; Cheng Shen

doi:10.31083/j.fbl2803045

Astragaloside IV Inhibits NLRP3 Inflammasome-Mediated Pyroptosis via Activation of Nrf-2/HO-1 Signaling Pathway and Protects against Doxorubicin-Induced Cardiac Dysfunction

Front Biosci (Landmark Ed). 2023 Mar 3;28(3):45. doi: 10.31083/j.fbl2803045.

Authors

Xueheng Chen^{1

2}, Chao Tian^{1

2}, Zhiqiang Zhang^{1

2}, Yiran Qin³, Runqi Meng^{1

2}, Xuening Dai^{1

2}, Yuanyuan Zhong^{1

2}, Xiqing Wei^{1

2}, Jinguo Zhang^{1

2}, Cheng Shen^{1

2}

Affiliations

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.

PMID: 37005753
DOI: 10.31083/j.fbl2803045

Abstract

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.

Keywords: Astragalus membranaceus; Nrf-2/HO-1; cardiac dysfunction; cardioprotection; doxorubicin; pyroptosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Doxorubicin / toxicity
Heart Diseases* / metabolism
Heme Oxygenase-1
Humans
Inflammasomes / metabolism
Interleukin-18 / metabolism
Interleukin-18 / pharmacology
Myocytes, Cardiac / metabolism
NF-E2-Related Factor 2 / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Oxidative Stress
Pyroptosis*
Signal Transduction

Substances

NF-E2-Related Factor 2
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Interleukin-18
astragaloside A
Heme Oxygenase-1
Doxorubicin