title: Glucocorticoids Suppress Mitochondrial Oxidant Production via Upregulation of Uncoupling Protein 2 in Hyperglycemic Endothelial Cells.
abstract: Diabetic complications are the leading cause of morbidity and mortality in diabetic patients. Elevated blood glucose contributes to the development of endothelial and vascular dysfunction, and, consequently, to diabetic micro- and macrovascular complications, because it increases the mitochondrial proton gradient and mitochondrial oxidant production. Therapeutic approaches designed to counteract glucose-induced mitochondrial reactive oxygen species (ROS) production in the vasculature are expected to show efficacy against all diabetic complications, but direct pharmacological targeting (scavenging) of mitochondrial oxidants remains challenging due to the high reactivity of some of these oxidant species. In a recent study, we have conducted a medium-throughput cell-based screening of a focused library of well-annotated pharmacologically active compounds and identified glucocorticoids as inhibitors of mitochondrial superoxide production in microvascular endothelial cells exposed to elevated extracellular glucose. The goal of the current study was to investigate the mechanism of glucocorticoids' action. Our findings show that glucocorticoids induce the expression of the mitochondrial UCP2 protein and decrease the mitochondrial potential. UCP2 silencing prevents the protective effect of the glucocorticoids on ROS production. UCP2 induction also increases the oxygen consumption and the "proton leak" in microvascular endothelial cells. Furthermore, glutamine supplementation augments the effect of glucocorticoids via further enhancing the expression of UCP2 at the translational level. We conclude that UCP2 induction represents a novel experimental therapeutic intervention in diabetic vascular complications. While direct repurposing of glucocorticoids may not be possible for the therapy of diabetic complications due to their significant side effects that develop during chronic administration, the UCP2 pathway may be therapeutically targetable by other, glucocorticoid-independent pharmacological means.
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.|University of Exeter Medical School, Exeter, United Kingdom.
authors.forename: Domokos
authors.identifier: 0000-0002-3132-3465
authors.initials: D
authors.lastname: Gerö
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
mesh_terms: D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D055808:Drug Discovery; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D015735:Mifepristone; D003907:Dexamethasone