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^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,*

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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: zhangjinguo@mail.jnmc.edu.cn (Jinguo Zhang); shencheng1117@126.com (Cheng Shen)

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

Submitted: 19 October 2022 | Revised: 13 December 2022 | Accepted: 14 December 2022 | Published: 3 March 2023

This is an open access article under the CC BY 4.0 license.

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-1 $\beta{}$ , 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-1 $\beta{}$ , 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

doxorubicin

pyroptosis

Nrf-2/HO-1

cardiac dysfunction

cardioprotection

Funding

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

Figures

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Fig. 1.

AS-IV attenuates DOX-induced cardiac dysfunction. (A) Representative M-mode images of echocardiograms of experimental animals in each group. (B) Quantitative analysis of left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF). (C) Quantitative analysis of left ventricular internal dimension at end-diastole (LVIDd) and left ventricular internal dimension at end-systole (LVIDs). (D) Quantitative analysis of serum concentration of brain natriuretic peptide (BNP), creatine kinase isoenzyme (CK-MB), cardiac troponin I (cTnI) and lactate dehydrogenase (LDH). CON, mice treated with an equal volume of saline. AS-IV, mice treated with 40 mg/kg AS-IV. DOX, mice treated with 2 mg/kg BW doxorubicin every other day with a cumulative dosage of 28 mg/kg. DOX + AS-IV, mice treated with doxorubicin and AS-IV. Data are shown as mean $\pm{}$ SEM, N = 3–10, * p $<$ 0.05, ** p $<$ 0.01, *** p $<$ 0.001, **** p $<$ 0.0001. Using Shapiro-Wilk test to test the normality of the distribution, all the data are in accordance with the normal distribution. All the data were compared by one-way analysis of variance followed by Tukey post-hoc test for multiple comparisons.

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