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Mitochondria in Vascular Health and Disease Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Dromparis, Peter R
Supervisor and department
Michelakis, Evangelos (Medicine)
Examining committee member and department
Dyck, Jason (Pediatrics)
Lopaschuk, Gary (Pharmacology)
Ganton, John (Medicine)
McMurtry, Michael (Medicine)
Department of Medicine

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Mitochondria generate reactive oxygen species (mROS) and metabolic substrates like alpha-ketogluterate (αKG), in proportion to oxygen, which target extra-mitochondrial effectors to coordinate a cellular response. For example, acute hypoxia decreases mROS, resulting in pulmonary artery smooth muscle cell (PASMC) contraction and hypoxic pulmonary vasoconstriction. Metabolic suppression can mimic the hypoxic effects, even in normoxia. In cancer, which has suppressed mitochondrial glucose oxidation (GO), reduced mitochondrial-derived signals including mROS and αKG stabilize hypoxia inducible factor 1α (HIF1α), resulting in normoxic activation that contributes to apoptosis resistance and angiogenesis. This metabolic suppression is shared with hyperproliferative and anti-apoptotic cells in the distal pulmonary artery (PA) wall, and is the hallmark of pulmonary arterial hypertension (PHT). Recently, we proposed that endoplasmic reticulum (ER)-stress-induced disruption of an ‘ER-mitochondrial unit’ as a PHT trigger, since the ER provides Ca2+ that is required for many of the key mitochondrial metabolic enzymes like pyruvate dehydrogenase (PDH) and Krebs cycle enzymes like isocitrate dehydrogenase (IDH; produces αKG). We show that like ER-stress, loss of uncoupling protein-2 (UCP2), reduces mitochondrial calcium (Ca2+m) in PASMCs. This suppresses PDH activity, Krebs cycle function and mROS production, activating HIF1α and contributing to apoptosis resistance in vitro. Mice lacking UCP2 spontaneously develop PHT with distal PA remodeling similar to hypoxic wildtype mice (a standard PHT model). This is the first description of UCP2 influencing oxygen sensing and may open a new window for biomarker or therapeutic strategies. We also show targeting ER-stress is a viable therapeutic strategy in PHT. 4-phenylbutyric acid (PBA), a FDA approved chemical chaperone that facilitates protein folding and attenuates ER-stress. PBA prevented and reversed pulmonary vascular remodeling and PHT in chronic hypoxia and monocrotaline rodents. In isolated PASMCs, PBA, and a second chemical chaperone tauroursodeoxycholate maintained Ca2+m, normalizing PDH activity and mROS/αKG, reducing proliferation and inducing apoptosis in hypoxia (an ER-stress inducer). Thus, pathobiology linked with the functional dysregulation between mitochondria and other organelles can be therapeutically targeted. Finally, we show that mitochondrial activation with thiazolidinediones can impair HIF1α signaling in a hindlimb ischemia model, potentially explaining some of the adverse cardiovascular events in some patients with these drugs.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Dromparis P and Michelakis ED 2013. Annual Review of Physiology. 75:95-126.Dromparis P, Paulin R, Sutendra G, Stenson TH, Haromy A, and Michelakis ED 2013. Circulation. 127(1):115-125.

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