Posadino Anna Maria, Cossu Annalisa, Giordo Roberta, Zinellu Angelo, Sotgia Salvatore, Vardeu Antonella, Hoa Phu Thi, Nguyen Le Hong Van, Carru Ciriaco, Pintus Gianfranco
Department of Biomedical Sciences, University of Sassari, Sassari, Italy; Laboratory of Vascular Biology, University of Sassari, Sassari, Italy.
Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
Food Chem Toxicol. 2015 Apr;78:10-6. doi: 10.1016/j.fct.2015.01.017. Epub 2015 Feb 2.
Studies analyzing the impact of natural antioxidants (NA) on Endothelial Cells (ECs) have dramatically increased during the last years, since a deregulated ECs redox state is at the base of the onset and progression of several cardiovascular diseases. However, whether NA can provide cardiovascular benefits is still a controversial area of debate. Resveratrol (RES), a natural polyphenol found in grapes, is believed to provide cardiovascular benefits by virtue of its antioxidant effect on the endothelium. Here, we report that tissue-attainable doses of resveratrol increased the intracellular oxidative state, thus affecting mitochondrial membrane depolarization and inducing EC death. Cyclosporine A, a mitochondrial permeability transition pore inhibitor, prevented oxidative-mediated cell death, thus implicating mitochondria in resveratrol-induced EC impairment. The specific cytochrome P450 (CYP) 2C9 inhibitor, sulfaphenazole, counteracted both oxidative stress and mitochondrial membrane depolarization, providing EC protection against resveratrol-elicited pro-oxidant effects. Our findings strongly suggest that CYP2C9 mediates resveratrol-induced oxidative stress leading to mitochondria impairment and EC death.
在过去几年中，分析天然抗氧化剂（NA）对内皮细胞（ECs）影响的研究急剧增加，因为内皮细胞氧化还原状态失调是多种心血管疾病发生和发展的基础。然而，NA是否能带来心血管益处仍是一个有争议的辩论领域。白藜芦醇（RES）是一种在葡萄中发现的天然多酚，据信因其对内皮的抗氧化作用而具有心血管益处。在此，我们报告，可在组织中达到的白藜芦醇剂量会增加细胞内氧化状态，从而影响线粒体膜去极化并诱导内皮细胞死亡。线粒体通透性转换孔抑制剂环孢素A可防止氧化介导的细胞死亡，因此表明线粒体参与了白藜芦醇诱导的内皮细胞损伤。特异性细胞色素P450（CYP）2C9抑制剂磺胺苯吡唑可抵消氧化应激和线粒体膜去极化，为内皮细胞提供针对白藜芦醇引发的促氧化作用的保护。我们的研究结果强烈表明，CYP2C9介导白藜芦醇诱导的氧化应激，导致线粒体损伤和内皮细胞死亡。
