caa a22 4500 605543364 CHVBK 20210128100926.0 cr unu---uuuuu 210128e20150301xx s 000 0 eng 10.1007/s00109-015-1263-5 doi (NATIONALLICENCE)springer-10.1007/s00109-015-1263-5 Mitochondrial dynamics in pulmonary arterial hypertension [Elektronische Daten] [John Ryan, Asish Dasgupta, Jessica Huston, Kuang-Huieh Chen, Stephen Archer] Pulmonary arterial hypertension (PAH) is an idiopathic cardiopulmonary disease characterized by obstruction of small pulmonary arteries. Vascular obstruction is the consequence of excessive proliferation and apoptosis resistance of vascular cells, as well as inflammation, thrombosis, and vasoconstriction. Vascular obstruction increases the afterload faced by the right ventricle (RV), leading to RV failure. The proliferative, obstructive vasculopathy of PAH shares several mitochondrial abnormalities with cancer, notably a shift to aerobic glycolysis and mitochondrial fragmentation. Mitochondria in the pulmonary artery smooth muscle cell (PASMC) normally serve as oxygen sensors. In PAH, acquired mitochondrial abnormalities, including epigenetic silencing of superoxide dismutase (SOD2), disrupt oxygen sensing creating a pseudo-hypoxic environment characterized by normoxic activation of hypoxia-inducible factor-1α (HIF-1α). The resulting metabolic shift to aerobic glycolysis (the Warburg phenomenon) reflects inhibition of pyruvate dehydrogenase by pyruvate dehydrogenase kinases. In addition, altered mitochondrial dynamics result in mitochondrial fragmentation. The molecular basis of this structural change includes upregulation and activation of fission mediators, notably dynamin-related protein 1 (DRP-1), and downregulation of fusion mediators, especially mitofusin-2 (MFN2). These pathogenic mitochondrial abnormalities offer new therapeutic targets. Inhibition of mitotic fission or enhancement of fusion in PAH PASMC slows cell proliferation, causes cell cycle arrest, and induces apoptosis. DRP-1 inhibition or MFN2 gene therapy can regress PAH in experimental models of PAH. This review focuses on the etiology of mitochondrial fragmentation in PAH and explores the therapeutic implications of mitochondrial dynamics in the pulmonary vasculature and RV. Springer-Verlag Berlin Heidelberg, 2015 Apoptosis nationallicence Oxygen sensing nationallicence Dynamin-related protein 1 (DRP-1) nationallicence Mitofusin-2 nationallicence Cell proliferation nationallicence Ryan John Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA aut Dasgupta Asish Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., K7L 3N6, Kingston, ON, Canada aut Huston Jessica Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA aut Chen Kuang-Huieh Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., K7L 3N6, Kingston, ON, Canada aut Archer Stephen Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., K7L 3N6, Kingston, ON, Canada aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/3(2015-03-01), 229-242 0946-2716 93:3<229 2015 93 109 https://doi.org/10.1007/s00109-015-1263-5 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 review-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-015-1263-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Ryan John Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA aut NATIONALLICENCE 700 1- Dasgupta Asish Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., K7L 3N6, Kingston, ON, Canada aut NATIONALLICENCE 700 1- Huston Jessica Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA aut NATIONALLICENCE 700 1- Chen Kuang-Huieh Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., K7L 3N6, Kingston, ON, Canada aut NATIONALLICENCE 700 1- Archer Stephen Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., K7L 3N6, Kingston, ON, Canada aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/3(2015-03-01), 229-242 0946-2716 93:3<229 2015 93 109