title: Increased activity of mitochondrial uncoupling protein 2 improves stress resistance in cultured endothelial cells exposed in vitro to high glucose levels.
abstract: The endothelium is relatively independent of the mitochondrial energy supply, but mitochondria-derived ROS may play an important role in the development of many cardiovascular diseases. Energy-dissipating uncoupling proteins (UCPs) mediate free fatty acid-activated, purine nucleotide-inhibited proton conductance (uncoupling) in the inner mitochondrial membrane. We have described a functional characteristic and an antioxidative role for UCP2 in endothelial cells and isolated mitochondria and how this function is altered by long-term growth in high concentrations of glucose. Human umbilical vein endothelial cells (EA.hy926 line) were grown in media with either high (25 mM) or normal (5.5 mM) glucose concentrations. Under nonphosphorylating and phosphorylating conditions, UCP activity was significantly higher in mitochondria isolated from high glucose-treated cells. More pronounced control of the respiratory rate, membrane potential, and ROS by UCP2 was observed in these mitochondria. A greater UCP2-mediated decrease in ROS generation indicates an improved antioxidative role for UCP2 under high glucose conditions. Mitochondrial and nonmitochondrial ROS generations were significantly higher in high glucose-treated cells independent of UCP2 expression. UCP2 gene silencing led to elevated mitochondrial ROS formation and ICAM1 expression, especially in high glucose-cultured cells. UCP2 influenced endothelial cell viability and resistance to oxidative stress. Endothelial cells exposed to high glucose concentrations were significantly more resistant to peroxide. In these cells, the increased activity of UCP2 led to improved stress resistance and protection against acute oxidative stress. Our results indicate that endothelial UCP2 may function as a sensor and negative regulator of mitochondrial ROS production in response to hyperglycemia.
authors.affiliation: Laboratory of Bioenergetics, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Koziel
authors.affiliation: Laboratory of Bioenergetics, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Sobieraj
authors.affiliation: Laboratory of Bioenergetics, Adam Mickiewicz University, Poznan, Poland wiesiaj@amu.edu.pl.
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Jarmuszkiewicz
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D002470:Cell Survival; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D020868:Gene Silencing; D005947:Glucose / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013312:Stress, Physiological; D013549:Sweetening Agents / Q000494:pharmacology*; D000071246:Uncoupling Protein 2
chemical_list: C573420:ICAM1 protein, human; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D013549:Sweetening Agents; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D018799:Intercellular Adhesion Molecule-1; D005947:Glucose
keywords: antioxidative activity; bioenergetics; endothelium; high glucose levels; mitochondria; uncoupling protein