title: Attenuating endoplasmic reticulum stress as a novel therapeutic strategy in pulmonary hypertension.
abstract: BACKGROUND
  Evidence suggestive of endoplasmic reticulum (ER) stress in the pulmonary arteries of patients with pulmonary arterial hypertension has been described for decades but has never been therapeutically targeted. ER stress is a feature of many conditions associated with pulmonary arterial hypertension like hypoxia, inflammation, or loss-of-function mutations. ER stress signaling in the pulmonary circulation involves the activation of activating transcription factor 6, which, via induction of the reticulin protein Nogo, can lead to the disruption of the functional ER-mitochondria unit and the increasingly recognized cancer-like metabolic shift in pulmonary arterial hypertension that promotes proliferation and apoptosis resistance in the pulmonary artery wall. We hypothesized that chemical chaperones known to suppress ER stress signaling, like 4-phenylbutyrate (PBA) or tauroursodeoxycholic acid, will inhibit the disruption of the ER-mitochondrial unit and prevent/reverse pulmonary arterial hypertension.
  
  
  RESULTS
  PBA in the drinking water both prevented and reversed chronic hypoxia-induced pulmonary hypertension in mice, decreasing pulmonary vascular resistance, pulmonary artery remodeling, and right ventricular hypertrophy and improving functional capacity without affecting systemic hemodynamics. These results were replicated in the monocrotaline rat model. PBA and tauroursodeoxycholic acid improved ER stress indexes in vivo and in vitro, decreased activating transcription factor 6 activation (cleavage, nuclear localization, luciferase, and downstream target expression), and inhibited the hypoxia-induced decrease in mitochondrial calcium and mitochondrial function. In addition, these chemical chaperones suppressed proliferation and induced apoptosis in pulmonary artery smooth muscle cells in vitro and in vivo.
  
  
  CONCLUSIONS
  Attenuating ER stress with clinically used chemical chaperones may be a novel therapeutic strategy in pulmonary hypertension with high translational potential.
authors.affiliation: Department of Medicine Cardiology, University of Alberta, Edmonton, AB, Canada T6G 2B7.
authors.forename: Peter
authors.initials: P
authors.lastname: Dromparis
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.forename: Trevor H
authors.initials: TH
authors.lastname: Stenson
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.forename: Gopinath
authors.initials: G
authors.lastname: Sutendra
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002756:Cholagogues and Choleretics / Q000378:metabolism / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism* / Q000517:prevention & control; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D008955:Models, Cardiovascular; D010654:Phenylbutyrates / Q000378:metabolism / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013655:Taurochenodeoxycholic Acid / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D051702:Activating Transcription Factor 6; D000970:Antineoplastic Agents; C497112:Atf6 protein, mouse; C497113:Atf6 protein, rat; D002756:Cholagogues and Choleretics; D010654:Phenylbutyrates; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid