Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
Atherosclerosis. 2012 Nov;225(1):83-90. doi: 10.1016/j.atherosclerosis.2012.08.023. Epub 2012 Aug 24.
Oxidative stress has been implicated as a causative factor of atherosclerosis. Defense systems against oxidative stress are maintained by radical scavenging antioxidants and/or by regulating the expression of antioxidant genes by activating oxidative stress-sensitive transcription factor: nuclear factor (erythroid-derived 2)-like 2 (Nrf2). We investigated the anti-atherogenic effects of three synthesized compounds (shogaol A: radical scavenging antioxidant activity; shogaol N: Nrf2-activating activity; shogaol N + A: both activities) and curcumin (both activities) in apolipoprotein E (apoE)-deficient mice. We expected compounds with both activities to have additive or synergistic anti-atherogenic effects; however, atherosclerosis was exacerbated significantly by curcumin and slightly by shogaol N + A. Shogaol A, shogaol N, and shogaol N + A showed no significant effect on atherosclerosis development. Immunohistochemical analysis of the aorta revealed that expression of CD36, an Nrf2-regulated gene, was strongly induced by treatment with curcumin. The total antioxidant capacity of plasma collected from mice administered the three compounds was evaluated using a hydrophilic probe, pyranine. Shogaol N or shogaol N + A significantly enhanced the antioxidant capacity of plasma, whereas shogaol A and curcumin did not show this activity. The concentrations of the three shogaol derivatives in plasma were similar (approximately 100 nM), while that of curcumin was much lower. These results suggest that plasma antioxidant capacity is maintained at high levels via Nrf2 activation and that CD36 expression enhances atherosclerosis development.
氧化应激被认为是动脉粥样硬化的一个致病因素。抗氧化应激的防御系统是通过自由基清除抗氧化剂来维持的，或者通过激活氧化应激敏感转录因子：核因子（红系衍生 2）样 2（Nrf2）来调节抗氧化基因的表达。我们研究了三种合成化合物（姜辣素 A：自由基清除抗氧化活性；姜辣素 N：Nrf2 激活活性；姜辣素 N+A：两种活性）和姜黄素（两种活性）在载脂蛋白 E（apoE）缺陷小鼠中的抗动脉粥样硬化作用。我们期望具有两种活性的化合物具有相加或协同的抗动脉粥样硬化作用；然而，姜黄素和姜辣素 N+A 显著加剧了动脉粥样硬化。姜辣素 A、姜辣素 N 和姜辣素 N+A 对动脉粥样硬化的发展没有显著影响。主动脉的免疫组织化学分析表明，Nrf2 调节的基因 CD36 的表达被姜黄素强烈诱导。用亲水性探针吡嗪评估从给予三种化合物的小鼠收集的血浆的总抗氧化能力。姜辣素 N 或姜辣素 N+A 显著增强了血浆的抗氧化能力，而姜辣素 A 和姜黄素没有显示这种活性。三种姜辣素衍生物在血浆中的浓度相似（约 100 nM），而姜黄素的浓度要低得多。这些结果表明，通过 Nrf2 激活维持了高水平的血浆抗氧化能力，并且 CD36 表达增强了动脉粥样硬化的发展。
