Mitochondria in Vascular Health and Disease

• Author / Creator

  Dromparis, Peter R

• 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.

• Subjects / Keywords

  • Mitochondria

• Graduation date

  Spring 2013

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3FN11134

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.