2. Academic Validation
  3. Oxymatrine alleviates ALD-induced cardiac hypertrophy by regulating autophagy via activation Nrf2/SIRT3 signaling pathway

Oxymatrine alleviates ALD-induced cardiac hypertrophy by regulating autophagy via activation Nrf2/SIRT3 signaling pathway

  • Phytomedicine. 2025 Mar:138:156389. doi: 10.1016/j.phymed.2025.156389.
Dingchun Lu 1,  Shun Wu 1,  Xueting Wang 1,  Jian Zhang 1,  Yini Xu 1,  Ling Tao 2,  Xiangchun Shen 3
Affiliations

Affiliations

  • 1 The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The Department of Pharmacology of Materia Medica, School of Pharmaceutical Sciences, Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China.
  • 2 The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The Department of Pharmacology of Materia Medica, School of Pharmaceutical Sciences, Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China. Electronic address: taoling@gmc.edu.cn.
  • 3 The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The Department of Pharmacology of Materia Medica, School of Pharmaceutical Sciences, Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China. Electronic address: shenxiangchun@126.com.
PMID: 39827815 DOI: 10.1016/j.phymed.2025.156389
Abstract

Background: Cardiac hypertrophy is a prevalent early pathological manifestation in various cardiovascular diseases, lacking effective interventions to impede its progression. Although oxymatrine (OMT) has shown potential benefits for cardiac function, its therapeutic efficacy and mechanism in cardiac hypertrophy remain incompletely understood. Notably, mitochondrial damage and dysregulated Autophagy are pivotal pathogenic mechanisms in cardiac hypertrophy.

Purpose: We investigate the pharmacological characteristics and mechanism of OMT in mitochondrial function and Autophagy in cardiac hypertrophy.

Study design and methods: A murine model of cardiac hypertrophy was induced by aldosterone in combination with high-salt drinking water, while primary cardiomyocyte hypertrophy was induced by aldosterone in vitro. Cardiac hypertrophy was assessed using echocardiography and histopathological staining. Autophagosomes and mitochondrial morphology were visualized by transmission electron microscopy. Levels of Reactive Oxygen Species (ROS), malondialdehyde (MDA), and adenosine triphosphate (ATP) were quantified using commercial kits. The binding affinity of OMT with Nrf2 was assessed through molecular docking. Furthermore, adenovirus, agonists, and inhibitors were employed to modulate Nrf2, followed by quantitative real-time polymerase chain reaction (qRT-PCR), immunoblotting, co-immunoprecipitation, chromatin immunoprecipitation, immunohistochemistry, and cellular thermal shift assay.

Results: OMT effectively attenuated aldosterone-induced cardiac hypertrophy both in vivo and in vitro. OMT promoted the activation of Nrf2, leading to elevated SIRT3 expression and enhanced autophagolysosome fusion, thereby modulating Mitophagy and improving mitochondrial function. Moreover, the cardioprotective effects of OMT were abolished upon silencing or inhibition of Nrf2. OMT binds to Nrf2, facilitating its dissociation and nuclear translocation.

Conclusion: OMT activates Nrf2, consequently enhancing SIRT3 transcription, restoring autophagic flux, and preserving mitochondrial integrity, thereby mitigating aldosterone-induced cardiac hypertrophy. In summary, our study is the first to discover and confirm that OMT can stabilize Nrf2, promoting its activation and subsequently up-regulating SIRT3, which in turn facilitates mitochondrial Autophagy. Additionally, PARKIN appears to play a key role in SIRT3-mediated regulation of Mitophagy, warranting further investigation.

Keywords

Autophagy; Cardiac hypertrophy; Mitochondria; Nrf2; Oxymatrine.

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