堪非醇通过 HDAC3 介导的 Nrf2 信号通路减少氧化应激，从而减轻心肌缺血损伤

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research Pub Date : 2024-11-05 DOI:10.1016/j.jare.2024.10.037

Zejun Yue, Yirong Zhang, Wei Zhang, Nanbo Zheng, Jiazeng Wen, Lingxuan Ren, XiaoYu Rong, Liang Bai, Rong Wang, Sihai Zhao, Enqi Liu, Weirong Wang

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引用次数: 0

摘要

导言堪非醇（KAE）是一种存在于多种植物中的类黄酮。最近的研究表明，从膳食中摄入大量 KAE 与降低心肌梗死的风险有关；然而，KAE 的心脏保护机制仍不清楚。方法用不同剂量的 KAE 预处理雄性大鼠 14 天，然后注射 ISO 诱导心肌缺血损伤。结果我们发现，KAE 预处理能显著减轻 ISO 注射大鼠的心肌损伤并改善心功能。此外，KAE 还通过降低丙二醛浓度、提高超氧化物歧化酶活性和保护心肌线粒体结构来减轻心肌缺血大鼠的氧化应激。KAE 还能通过抑制氧化应激减轻 CoCl2 诱导的 H9c2 心肌细胞损伤。在机制方面，我们发现 KAE 下调了 ISO 诱导的大鼠和 CoCl2 刺激的心肌细胞中 HDAC3 的表达，并上调了 Nrf2 的表达。用 HDAC3 选择性抑制剂 RGFP966 培养心肌细胞可增强 KAE 的保护作用并减少氧化应激。相反，与 KAE 处理组相比，通过腺病毒过表达 HDAC3 可减轻 KAE 对氧化应激的影响。在使用 RGFP966 或过表达 HDAC3 的腺病毒的心肌细胞中，HDAC3 还能调控 Nrf2 的表达；但抑制 Nrf2 会降低 KAE 对 CoCl2 诱导的心肌细胞中 ROS 生成的影响。免疫沉淀分析表明，HDAC3 与心肌细胞中的 Nrf2 相互作用。结论我们的数据表明，KAE 可通过 HDAC3 介导的 Nrf2 信号通路减少心肌细胞中的氧化应激，从而改善心脏损伤。

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Kaempferol alleviates myocardial ischemia injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway

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Kaempferol alleviates myocardial ischemia injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway

Introduction

Kaempferol (KAE) is a flavonoid found in various plants. Recent studies showed that high dietary intake of KAE was associated with a lower risk of myocardial infarction; however, the cardioprotective mechanism of KAE remains unknown.

Objectives

To determine the effect of KAE on cardiac injury in isoproterenol (ISO)-induced rats and cobalt chloride (CoCl₂)-treated cardiomyocytes, and the underlying mechanisms.

Methods

Male rats were pretreated with different doses of KAE for 14 days, and then injected with ISO to induce myocardial ischemia injury. We also established a model of myocardial cell injury using rat H9c2 cardiomyocytes stimulated with CoCl₂.

Results

We found that KAE pretreatment significantly alleviated myocardial injury and improved cardiac function in ISO-injected rats. In addition, KAE reduced oxidative stress in rats with myocardial ischemia by decreasing malondialdehyde concentration and increasing superoxide dismutase activity, and protection of the myocardial mitochondrial structure. KAE also attenuated CoCl₂-induced injury of H9c2 cardiomyocytes via suppression of oxidative stress. With regard to the mechanism, we found that KAE down-regulated HDAC3 expression and up-regulated Nrf2 expression in ISO-induced rats and CoCl₂-stimulated cardiomyocytes. Incubation of cardiomyocytes with HDAC3-selective inhibitor RGFP966 augmented the protective effect of KAE and reduced oxidative stress. By contrast, HDAC3 overexpression by adenovirus attenuated the effect of KAE on oxidative stress compared with KAE treatment group. HDAC3 also regulated Nrf2 expression in the cardiomyocytes with RGFP966 or an adenovirus overexpressing HDAC3; but Nrf2 inhibition reduced the effect of KAE on ROS generation in CoCl₂-induced cardiomyocytes. Immunoprecipitation assay showed that HDAC3 interacted with Nrf2 in cardiomyocytes. Further studies found that KAE increased the acetylation level of Nrf2, while HDAC3 overexpression decreased the acetylation of Nrf2 compared with KAE treatment group.

Conclusion

Our data show that KAE ameliorates cardiac injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway in cardiomyocytes.

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来源期刊

Journal of Advanced Research Multidisciplinary-Multidisciplinary

CiteScore

21.60

自引率

0.90%

发文量

280

审稿时长

12 weeks

期刊介绍： Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences. The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.