title: Coumaric acid induces mitochondrial damage and oxidative-mediated cell death of human endothelial cells.
abstract: Evidence that higher natural antioxidants (NA) intake provides cardiovascular protection is contradictory. The endothelium plays a pivotal role in cardiovascular homeostasis, and for this reason, the molecular events resulting from the interaction of NA with endothelial cells (ECs) are actively investigated. Here, we show that moderately high doses of coumaric acid (CA) induced intracellular reactive oxygen species (ROS) production, mitochondrial membrane depolarization and ECs death. Treatment of ECs with cyclosporine A, a mitochondrial permeability transition pore inhibitor, prevented the oxidative-mediated cell damage indicating mitochondrial involvement in CA-induced ECs impairment. CA-induced intracellular ROS generation was counteracted by the specific cytochrome P450 (CYP) 2C9 inhibitor sulfaphenazole (SPZ). SPZ also prevented CA-induced mitochondrial membrane depolarization and ECs death, implicating CYP2C9 in mediating the cellular response upon CA treatment. Our results indicate that moderately high doses of CA can promote CYP2C9-mediated oxidative stress eliciting mitochondrial-dependent ECs death and may pave the way toward mechanistic insight into NA effects on cardiovascular cells.
authors.affiliation: Department of Biomedical Sciences, University of Sassari, Viale San Pietro 34/B, 07100, Sassari, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Posadino
authors.forename: Annalisa
authors.initials: A
authors.lastname: Cossu
authors.forename: Roberta
authors.initials: R
authors.lastname: Giordo
authors.forename: Angelo
authors.initials: A
authors.lastname: Zinellu
authors.forename: Salvatore
authors.initials: S
authors.lastname: Sotgia
authors.forename: Antonella
authors.initials: A
authors.lastname: Vardeu
authors.forename: Phu Thi
authors.initials: PT
authors.lastname: Hoa
authors.forename: Luca
authors.initials: L
authors.lastname: Deiana
authors.forename: Ciriaco
authors.initials: C
authors.lastname: Carru
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pintus
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003373:Coumaric Acids / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D065729:Cytochrome P-450 CYP2C9; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013426:Sulfaphenazole / Q000494:pharmacology
chemical_list: D003373:Coumaric Acids; D017382:Reactive Oxygen Species; D013426:Sulfaphenazole; D016572:Cyclosporine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases