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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2014     Display Documents

ID: 682168.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2014
Mitochondrial hyperpolarization in pulmonary vascular remodeling. Mitochondrial uncoupling protein deficiency as disease model
Authors:Pak, O.; Sommer, N.; Hoeres, T.; Bakr, A.; Waisbrod, S.; Sydykov, A.; Haag, D.; Esfandiary, A.; Kojonazarov, B.; Veit, F.; Fuchs, B.; Weisel, F. C.; Hecker, M.; Schermuly, R. T.; Grimminger, F.; Ghofrani, H. A.; Seeger, W.; Weissmann, N.
Date of Publication (YYYY-MM-DD):2013-09
Journal Abbrev.:Am J Respir Cell Mol Biol
Issue / Number:3
Start Page:358
End Page:367
Audience:Not Specified
Abstract / Description: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.
Free Keywords:Animals; Anoxia/genetics/metabolism/pathology; Benzimidazoles; Carbocyanines; Carbonyl Cyanide m-Chlorophenyl Hydrazone/analogs & derivatives/pharmacology; Disease Models, Animal; Fluorescent Dyes; Free Radical Scavengers/pharmacology; Gene Expression Regulation; Humans; Hypertension, Pulmonary/chemically induced/genetics/*metabolism/pathology; Ion Channels/antagonists & inhibitors/deficiency/*genetics/metabolism; Membrane Potential, Mitochondrial/drug effects/*genetics; Mice; Mitochondria/drug effects/*genetics/metabolism; Mitochondrial Proteins/antagonists & inhibitors/deficiency/*genetics/metabolism; Monocrotaline; Muscle, Smooth, Vascular/drug effects/metabolism/pathology; Myocytes, Smooth Muscle/drug effects/*metabolism/pathology; Primary Cell Culture; Pulmonary Artery/drug effects/metabolism/pathology; RNA, Small Interfering/genetics/metabolism; Rats; Reactive Oxygen Species/metabolism
External Publication Status:published
Document Type:Article
Communicated by:Svea Hümmer
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:ISSN:1535-4989 (Electronic) 1044-1549 (Linking) %R 10.1165/rcmb.2012-0361OC
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