Journalartikel
Autorenliste: Pak, Oleg; Sommer, Natascha; Hoeres, Timm; Bakr, Adel; Waisbrod, Sharon; Sydykov, Akylbek; Haag, Daniela; Esfandiary, Azadeh; Kojonazarov, Baktybek; Veit, Florian; Fuchs, Beate; Weisel, Friederike Christine; Hecker, Matthias; Schermuly, Ralph Theo; Grimminger, Friedrich; Ghofrani, Hossein Ardeschir; Seeger, Werner; Weissmann, Norbert
Jahr der Veröffentlichung: 2013
Seiten: 358-367
Zeitschrift: American Journal of Respiratory Cell and Molecular Biology
Bandnummer: 49
Heftnummer: 3
ISSN: 1044-1549
DOI Link: https://doi.org/10.1165/rcmb.2012-0361OC
Verlag: American Thoracic Society
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 PHinducedby exposure tomonocrotaline(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.
Zitierstile
Harvard-Zitierstil: Pak, O., Sommer, N., Hoeres, T., Bakr, A., Waisbrod, S., Sydykov, A., et al. (2013) Mitochondrial Hyperpolarization in Pulmonary Vascular Remodeling Mitochondrial Uncoupling Protein Deficiency as Disease Model, American Journal of Respiratory Cell and Molecular Biology, 49(3), pp. 358-367. https://doi.org/10.1165/rcmb.2012-0361OC
APA-Zitierstil: Pak, O., Sommer, N., Hoeres, T., Bakr, A., Waisbrod, S., Sydykov, A., Haag, D., Esfandiary, A., Kojonazarov, B., Veit, F., Fuchs, B., Weisel, F., Hecker, M., Schermuly, R., Grimminger, F., Ghofrani, H., Seeger, W., & Weissmann, N. (2013). Mitochondrial Hyperpolarization in Pulmonary Vascular Remodeling Mitochondrial Uncoupling Protein Deficiency as Disease Model. American Journal of Respiratory Cell and Molecular Biology. 49(3), 358-367. https://doi.org/10.1165/rcmb.2012-0361OC
Schlagwörter
ARTERIAL-HYPERTENSION; Mitochondrial membrane potential; Pulmonary hypertension; UCP2
