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

SIRT3 化学 线粒体 乙酰化 免疫印迹 药理学 氧化应激 兴奋剂 锡尔图因 生物 生物化学 受体 基因
作者
Xueting Wang,Hongkun Wu,Jiangfei An,Guangqiong Zhang,Yan Chen,Lingyun Fu,Ling Tao,Guiyou Liang,Xiangchun Shen
出处
期刊:Biomedicine & Pharmacotherapy [Elsevier BV]
卷期号:167: 115618-115618 被引量:8
标识
DOI:10.1016/j.biopha.2023.115618
摘要

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.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.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.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.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.
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