Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis

Hai ZOU; Mengyu ZHANG; Xue YANG; Huafeng SHOU; Zhenglin CHEN; Quanfeng ZHU; Ting LUO; Xiaozhou MOU; Xiaoyi CHEN

doi:10.1631/jzus.B2300691

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Research Article | Updated：2024-09-20

Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis
Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis
木犀草苷通过调节AMPK/SIRT3/Nrf2通路抑制阿霉素诱导的心肌细胞焦亡
Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) Vol. 25, Issue 9, Pages: 756-772(2024)
Affiliations：

1.Department of Critical Care Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China
2.Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
3.Xianghu Laboratory, Hangzhou 311231, China
4.Clinical Research Institute, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China
5.Center for Reproductive Medicine, Department of Gynecology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China
6.Graduate School of Zhejiang Chinese Medical University, Hangzhou 310053, China
7.State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Laboratory (Hangzhou) for Risk Assessment of Agricultural Products of Ministry of Agriculture, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
8.General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China
Funds：
DOI：10.1631/jzus.B2300691
CLC：
CSTR：
Published： 15 September 2024 ，

Published Online： 12 September 2024 ，

Received： 06 October 2023 ，

Revised： 17 December 2023 ，
Accepted：

邹海,张梦宇,杨雪等.木犀草苷通过调节AMPK/SIRT3/Nrf2通路抑制阿霉素诱导的心肌细胞焦亡[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(09):756-772.

Hai ZOU, Mengyu ZHANG, Xue YANG, et al. Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 25(9):756-772(2024)
邹海,张梦宇,杨雪等.木犀草苷通过调节AMPK/SIRT3/Nrf2通路抑制阿霉素诱导的心肌细胞焦亡[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(09):756-772. DOI： 10.1631/jzus.B2300691.

Hai ZOU, Mengyu ZHANG, Xue YANG, et al. Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 25(9):756-772(2024) DOI： 10.1631/jzus.B2300691.

摘要

阿霉素（DOX）是一种可用于治疗血液系统恶性肿瘤及实体瘤的常用化疗药物，但其临床应用受到明显的心脏毒性的限制。木犀草苷（Cyn）是一种存在于金银花中的类黄酮苷类化合物，具有调节炎症、细胞焦亡和氧化应激等潜在的生物学功能。本研究通过每周一次腹腔注射DOX（5 mg/kg）并连续注射三周以构建DOX诱导的心脏毒性（DI

C）小鼠模型，用于评估Cyn的作用。治疗组小鼠每两天给予右唑嗪、MCC950和Cyn处理。通过血液生化、组织病理学、免疫组织化学、定量反转录聚合酶链反应（RT-qPCR）和蛋白质印迹（western blotting）等方法探讨Cyn治疗对心脏的保护作用及其可能机制。研究结果显示，Cyn治疗在缓解DIC方面具有显著的效果，能在一定程度上有效缓解氧化应激，维持细胞凋亡平衡并增强小鼠心脏功能。上述这些作用主要通过调节核苷酸结合寡聚化结构域样受体蛋白3（

NLRP3

）、半胱氨酸天冬氨酸蛋白酶-1（

caspase-1

）和

GSDMD

等与焦亡相关基因的转录水平来实现。此外，机制研究表明，Cyn可以显著调节DOX诱导心肌损伤小鼠组织中关键基因5'-磷酸腺苷活化蛋白激酶（

AMPK

）、过氧化物酶体增殖物激活受体γ共激活剂-1α（

PGC-1α

）、去乙酰化酶Sirtuin3（

SIRT3

）和核因子-E2相关因子2（

Nrf2

）的表达，因此我们推测AMPK/SIRT3/Nrf2通路在对抗DOX诱导的心肌细胞损伤中起着核心作用。综上所述，本研究证实了Cyn通过调节AMPK/SIRT3/Nrf2通路在治疗DIC方面的潜力。

Abstract

Doxorubicin (DOX) is a commonly administered chemotherapy drug for treating hematological malignancies and solid tumors; however

its clinical application is limited by significant cardiotoxicity. Cynaroside (Cyn) is a flavonoid glycoside distributed in ho

neysuckle

with confirmed potential biological functions in regulating inflammation

pyroptosis

and oxidative stress. Herein

the effects of Cyn were evaluated in a DOX-induced cardiotoxicity (DIC) mouse model

which was established by intraperitoneal injections of DOX (5 mg/kg) once a week for three weeks. The mice in the treatment group received dexrazoxane

MCC950

and Cyn every two days. Blood biochemistry

histopathology

immunohistochemistry

reverse transcription-quantitative polymerase chain reaction (RT-qPCR)

and western blotting were conducted to investigate the cardioprotective effects and potential mechanisms of Cyn treatment. The results demonstrated the significant benefits of Cyn treatment in mitigating DIC; it could effectively alleviate oxidative stress to a certain extent

maintain the equilibrium of cell apoptosis

and enhance the cardiac function of mice. These effects were realized via regulating the transcription levels of pyroptosis-related genes

such as nucleotide-binding oligomerization domain-like receptor protein 3 (

NLRP3

)

caspase-1

and gasdermin D (

GSDMD

). Mechanistically

for DOX-induced myocardial injury

Cyn could significantly modulate the expression of pivotal genes

including adenosine monophosphate-activated protein kinase (

AMPK

)

peroxisome proliferator-activated receptor γ coactivator-1α (

PGC-1α

)

sirtuin 3 (

SIRT3

)

and nuclear factor erythroid 2-related factor 2 (

Nrf2

). We attribute it to the mediation of AMPK/SIRT3/Nrf2 pathway

which plays a central role in preventing DOX-induced cardiomyocyte injury. In conclusion

the present study confirms the therapeutic potential of Cyn in DIC by regulating the AMPK/SIRT3/Nrf2 pathway.

关键词

木犀草苷阿霉素焦亡心脏毒性氧化应激

Keywords

CynarosideDoxorubicinPyroptosisCardiotoxicityOxidative stress

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