阿扎呋喃通过激活 Nrf2-ARE 通路对大鼠心肌损伤的心脏保护作用。
Cardioprotective role of azafrin in against myocardial injury in rats via activation of the Nrf2-ARE pathway.
机构信息
The MOE Key Laboratory of Standardization of Chinese Medicines and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai 201203, PR China.
The MOE Key Laboratory of Standardization of Chinese Medicines and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai 201203, PR China.
出版信息
Phytomedicine. 2018 Aug 1;47:12-22. doi: 10.1016/j.phymed.2018.04.042. Epub 2018 Apr 18.
BACKGROUND
The root of Centranthera grandiflora Benth. is a Chinese ethnodrug known as Ye-Can-Dou-Gen (YCDG) and has been widely used to treat cardiovascular diseases in Hmong, Yunnan Province, China; however, its mechanisms of action were largely unknown. Azafrin, a natural carotenoid, is one of the most abundant active ingredients in YCDG.
PURPOSE
We aimed to explore the cardioprotective effects of azafrin on myocardial infarction (MI) and myocardial ischaemia-reperfusion (MIR) injury and to clarify its underlying myocardial protective mechanisms.
METHODS
The in vitro cardioprotective effects of azafrin against oxidative stress injury in H9c2 cells were assessed by the ferric reducing antioxidant power (FRAP) assay and a viability assay in the presence of HO-induced oxidative insults, whereas the in vivo effects were assessed with the echocardiographic and histopathological evaluation together with 2,3,5-triphenyltetrazolium chloride (TTC) and serum biochemical analyses in vivo. Then, we used the luciferase reporter gene assay to measure Nrf2 transcriptional activity in HEK 293 cells and analysed the expression levels of enzymes downstream of Nrf2-ARE signalling by q-PCR and western blotting.
RESULTS
Azafrin showed higher FRAP values than FeSO and exhibited prophylactic and therapeutic potency against HO-induced cell injury. Additionally, azafrin treatment dramatically improved cardiac function; ameliorated the infarct size and pathological changes in rats; decreased the levels of MDA, cTnI, and myocardial enzymes and elevated SOD activity in vivo. In addition, azafrin significantly elevated the transcriptional activity of Nrf2 in HEK 293 cells and up-regulated the mRNA expression levels of genes downstream of Nrf2-ARE pathway activation in H9c2 cells. Furthermore, the protein expression levels of HO-1 and NQO1 in the cytoplasm and Nrf2 in the nucleus were also up-regulated in both the in vivo and in vitro experiments.
CONCLUSION
Azafrin exhibited cardioprotective effects against myocardial injury via activation of the Nrf2-ARE pathway. As a natural carotenoid antioxidant, this molecule represents a promising cardioprotective adjuvant for the prophylaxis and treatment of ischaemic heart diseases.
背景
穿心莲的根是一种中国民族药物，被称为叶-灿-豆-根（YCDG），已被广泛用于治疗中国云南的苗族人群的心血管疾病；然而，其作用机制在很大程度上是未知的。阿扎呋喃是一种天然类胡萝卜素，是 YCDG 中最丰富的活性成分之一。
目的
本研究旨在探讨阿扎呋喃对心肌梗死（MI）和心肌缺血再灌注（MIR）损伤的心脏保护作用，并阐明其潜在的心肌保护机制。
方法
通过 FRAP 测定和 HO 诱导的氧化应激损伤存在时的活力测定，评估阿扎呋喃对 H9c2 细胞氧化应激损伤的体外心脏保护作用，而体内作用则通过超声心动图和组织病理学评估以及 2,3,5-三苯基氯化四氮唑（TTC）和血清生化分析进行评估。然后，我们使用荧光素酶报告基因测定法测量 HEK 293 细胞中的 Nrf2 转录活性，并通过 q-PCR 和 Western blot 分析 Nrf2-ARE 信号通路下游酶的表达水平。
结果
阿扎呋喃的 FRAP 值高于 FeSO，对 HO 诱导的细胞损伤具有预防和治疗作用。此外，阿扎呋喃治疗显著改善了心脏功能；改善了大鼠的梗死面积和病理变化；降低了 MDA、cTnI 和心肌酶的水平，并提高了体内 SOD 活性。此外，阿扎呋喃显著提高了 HEK 293 细胞中 Nrf2 的转录活性，并上调了 H9c2 细胞中 Nrf2-ARE 通路激活下游基因的 mRNA 表达水平。此外，在体内和体外实验中，细胞质中的 HO-1 和 NQO1 以及核中的 Nrf2 的蛋白表达水平也上调。
结论
阿扎呋喃通过激活 Nrf2-ARE 通路对心肌损伤表现出心脏保护作用。作为一种天然类胡萝卜素抗氧化剂，该分子代表了一种有前途的缺血性心脏病预防和治疗的心脏保护佐剂。
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