2. Academic Validation
  3. Nitidine chloride induces cardiac hypertrophy in mice by targeting autophagy-related 4B cysteine peptidase

Nitidine chloride induces cardiac hypertrophy in mice by targeting autophagy-related 4B cysteine peptidase

  • Acta Pharmacol Sin. 2022 Aug 19;1-12. doi: 10.1038/s41401-022-00968-6.
Yang Hong  # 1,  Wan-Qing Xu  # 1,  Jing Feng 1,  Han Lou 1,  Heng Liu 1,  Lei Wang 1,  Hao Cui 1,  Lin-Tong Jiang 1,  Ran-Chen Xu 1,  Heng-Hui Xu 1,  Min-Zhen Xie 2,  Yang Li 3,  Philipp Kopylov 4,  Qi Wang 5,  Yong Zhang 6 7 8
Affiliations

Affiliations

  • 1 Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
  • 2 Department of Medicinal Chemistry and Natural Medicinal Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
  • 3 Department of Pharmaceutical Analysis, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
  • 4 Department of Preventive and Emergency Cardiology, Sechenov First Moscow State Medical University, Moscow, 101-135, Russian Federation.
  • 5 Department of Medicinal Chemistry and Natural Medicinal Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081, China. wangqiby1987@hotmail.com.
  • 6 Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China. hmuzhangyong@hotmail.com.
  • 7 Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin, 150081, China. hmuzhangyong@hotmail.com.
  • 8 Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, 150086, China. hmuzhangyong@hotmail.com.
  • # Contributed equally.
PMID: 35986213 DOI: 10.1038/s41401-022-00968-6
Abstract

Nitidine chloride (NC) is a standard active component from the traditional Chinese medicine Zanthoxylum nitidum (Roxb.) DC. (ZN). NC has shown a variety of pharmacological activities including anti-tumor activity. As a number of anti-tumor drugs cause cardiotoxicity, herein we investigated whether NC exerted a cardiotoxic effect and the underlying mechanism. Aqueous extract of ZN (ZNE) was intraperitoneally injected into rats, while NC was injected into beagles and mice once daily for 4 weeks. Cardiac function was assessed using echocardiography. We showed that both ZNE administered in rats and NC administered in mice induced dose-dependent cardiac hypertrophy and dysfunction, whereas administration of NC at the middle and high dose caused death in Beagles. Consistently, we observed a reduction of cardiac Autophagy levels in NC-treated mice and neonatal mouse cardiomyocytes. Furthermore, we demonstrated that autophagy-related 4B cysteine peptidase (ATG4B) may be a potential target of NC, since overexpression of ATG4B reversed the cardiac hypertrophy and reduced Autophagy levels observed in NC-treated mice. We conclude that NC induces cardiac hypertrophy via ATG4B-mediated downregulation of Autophagy in mice. Thus, this study provides guidance for the safe clinical application of ZN and the use of NC as an anti-tumor drug.

Keywords

Zanthoxylum nitidum (Roxb.) DC; autophagy; autophagy-related 4B cysteine peptidase; cardiac hypertrophy; nitidine chloride; species-based differences.

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