title: Hypoxia-reoxygenation-induced mitochondrial damage and apoptosis in human endothelial cells are inhibited by vitamin C.
abstract: Hypoxia and hypoxia-reperfusion (H-R) play important roles in human pathophysiology because they occur in clinical conditions such as circulatory shock, myocardial ischemia, stroke, and organ transplantation. Reintroduction of oxygen to hypoxic cells during reperfusion causes an increase in generation of reactive oxygen species (ROS), which can alter cell signaling, and cause damage to lipids, proteins, and DNA leading to ischemia-reperfusion injury. Since vitamin C is a potent antioxidant and quenches ROS, we investigated the role of intracellular ascorbic acid (iAA) in endothelial cells undergoing hypoxia-reperfusion. Intracellular AA protected human endothelial cells from H-R-induced apoptosis. Intracellular AA also prevents loss of mitochondrial membrane potential and the release of cytochrome C and activation of caspase-9 and caspase-3 during H-R. Additionally, inhibition of caspase-9 activation prevented H-R-induced apoptosis, suggesting a mitochondrial site of initiation of apoptosis. We found that H-R induced an increase in ROS in endothelial cells that was abrogated in the presence of iAA. Our results indicate that vitamin C prevents hypoxia and H-R-induced damage to human endothelium.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. mascarem@mskcc.org
authors.forename: Manya
authors.initials: M
authors.lastname: Dhar-Mascareño
authors.forename: Juan M
authors.initials: JM
authors.lastname: Cárcamo
authors.forename: David W
authors.initials: DW
authors.lastname: Golde
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism
chemical_list: D000975:Antioxidants; D009004:Monosaccharide Transport Proteins; D017382:Reactive Oxygen Species; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005947:Glucose; D001205:Ascorbic Acid; D010100:Oxygen