Ying Zhekang, Chen Minjie, Xie Xiaoyun, Wang Xiaoke, Kherada Nisharahmed, Desikan Rajagopal, Mihai Georgeta, Burns Patrick, Sun Qinghua, Rajagopalan Sanjay
Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai, 200120, PR China.
Department of Medicine Cardiology Division, University of Maryland School of Medicine, Baltimore, Maryland, 21201, United States of America.
PLoS One. 2016 Feb 9;11(2):e0148305. doi: 10.1371/journal.pone.0148305. eCollection 2016.
Oxidative stress is implicated in the pathogenesis of atherosclerosis, and Nrf2 is the transcriptional factor central in cellular antioxidant responses. In the present study, we investigate the effect of a dihydrolipoic acid derivative lipoicmethylenedioxyphenol (LMDP) on the progression of atherosclerosis and test whether its effect on atherosclerosis is mediated by Nrf2.
Both magnetic resonance imaging (MRI) scanning and en face analysis reveal that 14 weeks of treatment with LMDP markedly reduced atherosclerotic burden in a rabbit balloon vascular injury model. Myograph analyses show decreased aortic contractile response to phenylephrine and increased aortic response to acetylcholine and insulin in LMDP-treated animals, suggesting that LMDP inhibits atherosclerosis through improving vascular function. A role of Nrf2 signaling in mediating the amelioration of vascular function by LMDP was supported by increased Nrf2 translocation into nuclear and increased expression of Nrf2 target genes. Furthermore, chemotaxis analysis with Boydem chamber shows that leukocytes isolated from LMDP-treated rabbits had reduced chemotaxis, and knock-down of Nrf2 significantly reduced the effect of LMDP on the chemotaxis of mouse macrophages.
Our results support that LMDP has an anti-atherosclerotic effect likely through activation of Nrf2 signaling and subsequent inhibition of macrophage chemotaxis.
氧化应激与动脉粥样硬化的发病机制有关，而Nrf2是细胞抗氧化反应的核心转录因子。在本研究中，我们研究了二氢硫辛酸衍生物硫辛酸亚甲基二氧苯酚（LMDP）对动脉粥样硬化进展的影响，并测试其对动脉粥样硬化的影响是否由Nrf2介导。
磁共振成像（MRI）扫描和正面分析均显示，在兔球囊血管损伤模型中，LMDP治疗14周可显著减轻动脉粥样硬化负担。肌动描记法分析表明，在接受LMDP治疗的动物中，主动脉对去氧肾上腺素的收缩反应降低，对乙酰胆碱和胰岛素的反应增加，这表明LMDP通过改善血管功能来抑制动脉粥样硬化。Nrf2易位至细胞核增加以及Nrf2靶基因表达增加，支持了Nrf2信号在介导LMDP改善血管功能中的作用。此外，使用Boydem小室进行的趋化性分析表明，从接受LMDP治疗的兔子分离出的白细胞趋化性降低，而敲低Nrf2可显著降低LMDP对小鼠巨噬细胞趋化性的影响。
我们的结果支持LMDP可能通过激活Nrf2信号并随后抑制巨噬细胞趋化性而具有抗动脉粥样硬化作用。
