2. Academic Validation
  3. Cyclovirobuxine D alleviates aldosterone-induced myocardial hypertrophy by protecting mitochondrial function depending on the mutual regulation of Nrf2-SIRT3

Cyclovirobuxine D alleviates aldosterone-induced myocardial hypertrophy by protecting mitochondrial function depending on the mutual regulation of Nrf2-SIRT3

  • Biomed Pharmacother. 2023 Oct 2:167:115618. doi: 10.1016/j.biopha.2023.115618.
Xueting Wang 1,  Hongkun Wu 2,  Jiangfei An 3,  Guangqiong Zhang 3,  Yan Chen 3,  Lingyun Fu 3,  Ling Tao 3,  Guiyou Liang 4,  Xiangchun Shen 5
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, Guian New District, 550025 Guizhou, China; Medical College, Guizhou University, Huaxi District, 550025 Guizhou, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guian New District, 550025 Guizhou, 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, Guian New District, 550025 Guizhou, China.
  • 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, Guian New District, 550025 Guizhou, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guian New District, 550025 Guizhou, China.
  • 4 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, Guian New District, 550025 Guizhou, China. Electronic address: [email protected].
  • 5 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, Guian New District, 550025 Guizhou, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guian New District, 550025 Guizhou, China. Electronic address: [email protected].
PMID: 37793277 DOI: 10.1016/j.biopha.2023.115618
Abstract

Background: Cyclovirobuxine D (CVB-D) is a natural alkaloid that exhibits multiple pharmacological activities, such as anti-inflammatory, anti-oxidative stress, and anti-cancer properties. However, its specific protective mechanism of action for myocardial hypertrophy remains unresolved.

Purpose: This work was to investigate the ameliorative impact of CVB-D in myocardial hypertrophy, and to elucidate aldosterone (ALD)-induced myocardial hypertrophy by inhibiting the SIRT3 mediated Nrf2 activation.

Methods: The myocardial hypertrophy model was reproduced by ALD both in vitro and in vivo, and the protective effect of CVB-D on myocardium and mitochondria was evaluated by TEM, H&E, qPCR, Western blot and ChIP. An immunoprecipitation experiment was adopted to evaluate the acetylation level of Nrf2 and the binding between SIRT3 and Nrf2. Additionally, bardoxolone-methyl (BAR, an Nrf2 agonist), ML385 (an Nrf2 inhibitor), resveratrol (RES, a SIRT3 agonist), and 3-TYP (a SIRT3 Inhibitor) were used to confirm the molecular mechanism of CVB-D. Lastly, a molecular docking technique was employed to predict the binding site of SIRT3 and Nrf2 proteins.

Results: Our findings suggested that CVB-D improved mitochondrial function, leading to a reduction in ALD-induced cardiomyocyte hypertrophy. By CVB-D treatment, there was an activation of mutual regulation between Nrf2 and SIRT3. Specifically, CVB-D resulted in the increase of Nrf2 protein in the nucleus and activated Nrf2 signaling pathway, thus up-regulating SIRT3. The activation of SIRT3 and the protective action of mitochondrion disappeared because of the intervention of ML385. After CVB-D activated SIRT3, the acetylation level of Nrf2 decreased, followed by activating the Nrf2 pathway. The activation of Nrf2 and mitochondrial protection by CVB-D were reversed by 3-TYP. Our results are also supported by Co-IP and molecular docking analysis, revealing that CVB-D promotes SIRT3-mediated Nrf2 activation.

Conclusion: Thus, CVB-D ameliorates ALD-induced myocardial hypertrophy by recovering mitochondrial function by activating the mutual regulation of Nrf2 and SIRT3. Thus, CVB-D could be a beneficial drug for myocardial hypertrophy.

Keywords

Cyclovirobuxine D; Mitochondria; Myocardial hypertrophy; Nrf2; SIRT3.

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