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A Metabolic Basis for Vascular Remodeling in Pulmonary Arterial Hypertension Open Access


Other title
Cell death
Pulmonary hypertension -- Animal models
Lungs -- Blood-vessels -- Diseases
Mitochondrial pathology -- Animal models
Pulmonary artery -- Abnormalities -- Research
Mitochondria -- Formation -- Inhibitors
Lungs -- Metabolism -- Regulation
Type of item
Degree grantor
University of Alberta
Author or creator
Sutendra, Gopinath
Supervisor and department
Michelakis, Evangelos (Medicine)
Examining committee member and department
Thebaud, Bernard (Pediatrics)
Petruk, Kenn (Surgery)
McMurtry, Michael Sean (Medicine)
Rabinovitch, Marlene (Stanford, Pediatrics)
Department of Medicine

Date accepted
Graduation date
Doctor of Philosophy
Degree level
In Pulmonary Arterial Hypertension (PAH), pro-constrictive, pro-proliferative and anti-apoptotic diatheses converge to produce contraction and excessive proliferation of pulmonary artery smooth muscle cells (PASMC), a hallmark of PAH-vascular remodeling. The increased afterload causes right ventricular (RV) dysfunction and early death. The resistance to apoptosis is critical in PAH pathology, resembling the suppressed apoptosis in cancer, but its cause is unknown. We show that the apoptosis resistance is associated with a specific metabolic phenotype and remodeled mitochondria, the organelles in which metabolism and apoptosis regulation converge. Suppression of the mitochondria-based glucose oxidation (GO) and increased glycolysis (Gly) in the cytoplasm is associated with an anti-apoptotic state in many diseases including cancer. We show that reversing this mitochondrial remodeling in PAH PASMCs using dichloroacetate (DCA, an inhibitor of the mitochondrial pyruvate dehydrogenase kinase, PDK, the gatekeeper of carbohydrate influx in the mitochondria) resulted in increased GO/Gly ratio and induction of apoptosis in PAH but not normal cells, reversing the vascular remodeling in vivo. In addition, we investigated the role of fatty acids (FA), the other major mitochondrial fuel in this metabolic remodeling. FA oxidation (FAO) and GO, both occurring at the mitochondria, are kept in balance through the “Randle cycle” feedback: GO is activated (through PDK inhibition) when FAO is suppressed. We set to explore the role of FAO in the mitochondrial and vascular remodeling in PAH and we discovered that in mice which lack malonyl-CoA-decarboxylase (MCD), an enzyme that activates FAO in mitochondria, produced a normal phenotype that was completely resistant to PAH. We also showed that similar to DCA, the FAO inhibitor trimetazidine (TMZ), also reversed established PAH in-vivo. We then investigated the signals resulting in suppressed mitochondrial function. We show that the endoplasmic reticulum (ER; an organelle that facilitates protein folding) and mitochondria unit was disrupted. Disruption of the unit resulted in decreased transfer of lipids and calcium from the ER to the mitochondria, resulting in mitochondrial suppression. In addition we showed that hypoxia induced ER stress, resulting in increased expression of the reticulon protein Nogo. Induction of Nogo resulted in an increased in the distance between the ER and mitochondria unit, mitochondrial suppression and apoptosis resistance. Nogo-deficient mice were resistant to the development of PAH. Finally, we explored the role of inflammation (which can also induce ER stress) in PAH and showed that treatment with Etanercept (a TNFα inhibitor) increased mitochondrial activity and attenuated an inflammatory rodent model of PAH. In conclusion, this work provides evidence for a generalized metabolic dysfunction in the pathogenesis of PAH which can be therapeutically targeted with mitochondrial activating drugs.
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