title: Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature.
abstract: In the pulmonary vasculature, the mechanisms responsible for oxygen sensing and the initiation of hypoxia-induced vasoconstriction and vascular remodeling are still unclear. Nitric oxide (NO) and reactive oxygen species (ROS) are discussed as early mediators of the hypoxic response. Here, we describe a quantitative analysis of NO- and ROS-producing cells within the vascular walls of murine lung sections cultured at normoxia or hypoxia. Whereas the number of NO-producing cells was not changed by hypoxia, the number of ROS-generating cells was significantly increased. Addition of specific inhibitors revealed that mitochondria were the source of ROS. The participation of the individual mitochondrial complexes differed in normoxic and hypoxic ROS generation. Whereas normoxic ROS production required complexes I and III, hypoxic ROS generation additionally demanded complex II. Histochemically demonstrable succinate dehydrogenase activity of complex II in the arterial wall decreased during hypoxia. Inhibition of the reversed enzymatic reaction, i.e., fumarate reductase, by application of succinate, specifically abolished hypoxic, but not normoxic, ROS generation. Thus complex II plays an essential role in hypoxic ROS production. Presumably, its catalytic activity switches from succinate dehydrogenase to fumarate reductase at reduced oxygen tension, thereby modulating the directionality of the electron flow.
authors.affiliation: Institute of Anatomy and Cell Biology, Justus Liebig University, 35385 Giessen, Germany. Renate.Paddenberg@anatomie.med.uni-giessen.de
authors.forename: Renate
authors.initials: R
authors.lastname: Paddenberg
authors.forename: Barat
authors.initials: B
authors.lastname: Ishaq
authors.forename: Anna
authors.initials: A
authors.lastname: Goldenberg
authors.forename: Petra
authors.initials: P
authors.lastname: Faulhammer
authors.forename: Frank
authors.initials: F
authors.lastname: Rose
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Ruediger C
authors.initials: RC
authors.lastname: Braun-Dullaeus
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kummer
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D004579:Electron Transport / Q000502:physiology; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009574:Nitro Compounds; D009924:Organ Culture Techniques; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019810:Sodium Azide / Q000494:pharmacology; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000959:Antihypertensive Agents; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009574:Nitro Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D013804:Thenoyltrifluoroacetone; D000968:Antimycin A; D019810:Sodium Azide; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D014450:Electron Transport Complex III; C015392:3-nitropropionic acid