Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2.
Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2.
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DOI：
10.1371/journal.pone.0025436
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zou MH
中科院分区：
文献类型：
--
作者：
Wang Q;Zhang M;Liang B;Shirwany N;Zhu Y;Zou MH
小檗碱是一种从黄连中纯化的植物生物碱，据报道可以激活amp活化蛋白激酶（AMPK）。小檗碱对心血管疾病的保护作用是否需要AMPK仍不清楚。本研究旨在确定AMPK是否在小檗碱诱导的体内氧化应激和动脉粥样硬化的减少中是必需的。饲喂西方饲料的ApoE （ApoE-/-）小鼠和ApoE-/-/AMPK α 2-/-小鼠用小檗碱治疗8周。在离体主动脉中评估动脉粥样硬化病变、解偶联蛋白2 （UCP2）的表达和氧化应激标志物。在ApoE-/-小鼠中，慢性给药小檗碱可显著降低主动脉病变，显著降低主动脉氧化应激和粘附分子表达，显著升高UCP2水平。相比之下，在ApoE-/-/AMPK α 2-/-小鼠中，小檗碱对这些终点的影响很小。在培养的人脐静脉内皮细胞（HUVECs）中，小檗碱以ampk依赖性的方式显著增加UCP2 mRNA和蛋白的表达。转染核呼吸因子1 （NRF1）特异性siRNA的HUVECs可减弱小檗碱诱导的UCP2表达，而转染对照siRNA则无此作用。最后，小檗碱促进线粒体生物发生，导致UCP2表达上调。我们得出结论，小檗碱可以减少氧化应激和血管炎症，并通过刺激ampk依赖性UCP2表达的机制抑制动脉粥样硬化。
Berberine, a botanical alkaloid purified from Coptidis rhizoma, is reported to activate the AMP-activated protein kinase (AMPK). Whether AMPK is required for the protective effects of berberine in cardiovascular diseases remains unknown. This study was designed to determine whether AMPK is required for berberine-induced reduction of oxidative stress and atherosclerosis in vivo. ApoE (ApoE-/-) mice and ApoE-/-/AMPK alpha 2-/- mice that were fed Western diets were treated with berberine for 8 weeks. Atherosclerotic aortic lesions, expression of uncoupling protein 2 (UCP2), and markers of oxidative stress were evaluated in isolated aortas. In ApoE-/- mice, chronic administration of berberine significantly reduced aortic lesions, markedly reduced oxidative stress and expression of adhesion molecules in aorta, and significantly increased UCP2 levels. In contrast, in ApoE-/-/AMPK alpha 2-/- mice, berberine had little effect on those endpoints. In cultured human umbilical vein endothelial cells (HUVECs), berberine significantly increased UCP2 mRNA and protein expression in an AMPK-dependent manner. Transfection of HUVECs with nuclear respiratory factor 1 (NRF1)-specific siRNA attenuated berberine-induced expression of UCP2, whereas transfection with control siRNA did not. Finally, berberine promoted mitochondrial biogenesis that contributed to up-regulation of UCP2 expression. We conclude that berberine reduces oxidative stress and vascular inflammation, and suppresses atherogenesis via a mechanism that includes stimulation of AMPK-dependent UCP2 expression.