Pak 2013 Am J Respir Cell Mol Biol

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Pak O, Sommer N, Hoeres T, Bakr A, Waisbrod S, Sydykov A, Haag D, Esfandiary A, Kojonazarov B, Veit F, Fuchs B, Weisel FC, Hecker M, Schermuly RT, Grimminger F, Ghofrani HA, Seeger W, Weissmann N (2013) Mitochondrial hyperpolarization in pulmonary vascular remodeling - UCP2 deficiency as disease model. Am J Respir Cell Mol Biol 49:358-67.

» PMID:23590303

Pak O, Sommer N, Hoeres T, Bakr A, Waisbrod S, Sydykov A, Haag D, Esfandiary A, Kojonazarov B, Veit F, Fuchs B, Weisel FC, Hecker M, Schermuly RT, Grimminger F, Ghofrani HA, Seeger W, Weissmann N (2013) Am J Respir Cell Mol Biol

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.

Keywords: Pulmonary hypertension, Mitochondria, Mitochondrial membrane potential, UCP2 (mitochondrial uncoupling protein 2), Reactive oxygen species

O2k-Network Lab: DE Giessen Weissmann N


Labels: MiParea: Respiration, mt-Membrane, Genetic knockout;overexpression, mt-Medicine  Pathology: Cardiovascular  Stress:Ischemia-reperfusion  Organism: Human, Rat  Tissue;cell: Lung;gill  Preparation: Intact cells 


Coupling state: LEAK, ROUTINE, ET  Pathway: N, S  HRR: Oxygraph-2k