title: Mitochondrial hyperpolarization in pulmonary vascular remodeling. Mitochondrial uncoupling protein deficiency as disease model.
abstract: Alterations of mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitochondrial respiration are possible triggers of pulmonary vascular remodeling in pulmonary hypertension (PH). We investigated the role of MMP in PH and hypothesized that deletion of the mitochondrial uncoupling protein 2 (UCP2) increases MMP, thus promoting pulmonary vascular remodeling and PH. MMP was measured by JC-1 in isolated pulmonary arterial smooth muscle cells (PASMCs) of patients with PH and animals with PH induced by exposure to monocrotaline (MCT) or chronic hypoxia. PH was quantified in vivo in UCP2-deficient (UCP2(-/-)) mice by hemodynamics, morphometry, and echocardiography. ROS were measured by electron spin resonance spectroscopy and proliferation by thymidine incorporation. Mitochondrial respiration was investigated by high-resolution respirometry. MMP was increased in PASMCs of patients and in animal models of PH. UCP2(-/-) mice exhibited pulmonary vascular remodeling and mild PH compared with wild-type (WT) mice. PASMCs of UCP2(-/-) mice showed increased proliferation, MMP, and ROS release. Increased proliferation of UCP2(-/-) PASMCs could be attenuated by ROS inhibitors and inhibited by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, which decreased MMP to the level of WT mice. Mitochondrial respiration was altered in PASMCs from MCT rats and PASMCs exposed to hypoxia but not in isolated pulmonary mitochondria of UCP2(-/-) mice or PASMCs after treatment with small interfering RNA for UCP2. Our data suggest that increased MMP causes vascular remodeling in UCP2(-/-) mice partially via increased ROS. In chronic hypoxia and MCT-induced PH, additional pathomechanisms such as decreased respiration may play a role.
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, University of Giessen and Marburg Lung Center, Justus-Liebig-University, Giessen, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Pak
authors.forename: Natascha
authors.initials: N
authors.lastname: Sommer
authors.forename: Timm
authors.initials: T
authors.lastname: Hoeres
authors.forename: Adel
authors.initials: A
authors.lastname: Bakr
authors.forename: Sharon
authors.initials: S
authors.lastname: Waisbrod
authors.forename: Akylbek
authors.initials: A
authors.lastname: Sydykov
authors.forename: Daniela
authors.initials: D
authors.lastname: Haag
authors.forename: Azadeh
authors.initials: A
authors.lastname: Esfandiary
authors.forename: Baktybek
authors.initials: B
authors.lastname: Kojonazarov
authors.forename: Florian
authors.initials: F
authors.lastname: Veit
authors.forename: Beate
authors.initials: B
authors.lastname: Fuchs
authors.forename: Friederike Christine
authors.initials: FC
authors.lastname: Weisel
authors.forename: Matthias
authors.initials: M
authors.lastname: Hecker
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
mesh_terms: D000818:Animals; D001562:Benzimidazoles; D002232:Carbocyanines; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D001562:Benzimidazoles; D002232:Carbocyanines; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D007473:Ion Channels; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; C108897:carbonylcyanide 4-trifluoromethoxyphenylhydrazone; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D016686:Monocrotaline