title: The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension.
abstract: Pulmonary arterial hypertension (PAH) is caused by excessive proliferation of vascular cells, which occlude the lumen of pulmonary arteries (PAs) and lead to right ventricular failure. The cause of the vascular remodeling in PAH remains unknown, and the prognosis of PAH remains poor. Abnormal mitochondria in PAH PA smooth muscle cells (SMCs) suppress mitochondria-dependent apoptosis and contribute to the vascular remodeling. We hypothesized that early endoplasmic reticulum (ER) stress, which is associated with clinical triggers of PAH including hypoxia, bone morphogenetic protein receptor II mutations, and HIV/herpes simplex virus infections, explains the mitochondrial abnormalities and has a causal role in PAH. We showed in SMCs from mice that Nogo-B, a regulator of ER structure, was induced by hypoxia in SMCs of the PAs but not the systemic vasculature through activation of the ER stress-sensitive transcription factor ATF6. Nogo-B induction increased the distance between the ER and mitochondria and decreased ER-to-mitochondria phospholipid transfer and intramitochondrial calcium. In addition, we noted inhibition of calcium-sensitive mitochondrial enzymes, increased mitochondrial membrane potential, decreased mitochondrial reactive oxygen species, and decreased mitochondria-dependent apoptosis. Lack of Nogo-B in PASMCs from Nogo-A/B-/- mice prevented these hypoxia-induced changes in vitro and in vivo, resulting in complete resistance to PAH. Nogo-B in the serum and PAs of PAH patients was also increased. Therefore, triggers of PAH may induce Nogo-B, which disrupts the ER-mitochondria unit and suppresses apoptosis. This could rescue PASMCs from death during ER stress but enable the development of PAH through overproliferation. The disruption of the ER-mitochondria unit may be relevant to other diseases in which Nogo is implicated, such as cancer or neurodegeneration.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2B7, Canada.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Sutendra
authors.forename: Peter
authors.initials: P
authors.lastname: Dromparis
authors.forename: Paulette
authors.initials: P
authors.lastname: Wright
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Hao
authors.forename: M Sean
authors.initials: MS
authors.lastname: McMurtry
authors.forename: Marek
authors.initials: M
authors.lastname: Michalak
authors.forename: Jean E
authors.initials: JE
authors.lastname: Vance
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D000860:Hypoxia / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology; D050778:NFATC Transcription Factors / Q000378:metabolism; D000070798:Nogo Proteins; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051702:Activating Transcription Factor 6; D051793:Hypoxia-Inducible Factor 1; D009185:Myelin Proteins; D050778:NFATC Transcription Factors; D000070798:Nogo Proteins; D015221:Potassium Channels; C000603199:RTN4 protein, human; C000603201:Rtn4 protein, mouse