title: Resveratrol alters human endothelial cells redox state and causes mitochondrial-dependent cell death.
abstract: 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.
authors: Department of Biomedical Sciences, University of Sassari, Sassari, Italy; Laboratory of Vascular Biology, University of Sassari, Sassari, Italy.
authors: Anna Maria
authors: AM
authors: Posadino
authors: Department of Biomedical Sciences, University of Sassari, Sassari, Italy; Laboratory of Vascular Biology, University of Sassari, Sassari, Italy.
authors: Annalisa
authors: A
authors: Cossu
authors: Department of Biomedical Sciences, University of Sassari, Sassari, Italy; Laboratory of Vascular Biology, University of Sassari, Sassari, Italy.
authors: Roberta
authors: R
authors: Giordo
authors: Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
authors: Angelo
authors: A
authors: Zinellu
authors: Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
authors: Salvatore
authors: S
authors: Sotgia
authors: Department of Biomedical Sciences, University of Sassari, Sassari, Italy; Laboratory of Vascular Biology, University of Sassari, Sassari, Italy; Bristol Heart Institute, University of Bristol, Bristol, England, UK.
authors: Antonella
authors: A
authors: Vardeu
authors: Department of Biomedical Sciences, University of Sassari, Sassari, Italy; Laboratory of Vascular Biology, University of Sassari, Sassari, Italy; Department of Biochemistry, Huè University of Medicine and Pharmacy, Huè, Viet Nam.
authors: Phu Thi
authors: PT
authors: Hoa
authors: Department of Biomedical Sciences, University of Sassari, Sassari, Italy; Laboratory of Vascular Biology, University of Sassari, Sassari, Italy; Department of Biochemistry, Huè University of Medicine and Pharmacy, Huè, Viet Nam.
authors: Le Hong Van
authors: le HV
authors: Nguyen
authors: Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
authors: Ciriaco
authors: C
authors: Carru
authors: Department of Biomedical Sciences, University of Sassari, Sassari, Italy; Laboratory of Vascular Biology, University of Sassari, Sassari, Italy. Electronic address: gpintus@uniss.it.
authors: Gianfranco
authors: G
authors: Pintus
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D051336:Mitochondrial Membranes / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013426:Sulfaphenazole / Q000494:pharmacology
chemical_list: D065688:Cytochrome P-450 CYP2C9 Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D013267:Stilbenes; D013426:Sulfaphenazole; D016572:Cyclosporine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000077185:Resveratrol
keywords: Antioxidants; Cell damage; Endothelial cells; Pro-oxidant effect; Resveratrol