title: A critical role for the protein apoptosis repressor with caspase recruitment domain in hypoxia-induced pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is a lethal syndrome associated with the pathogenic remodeling of the pulmonary vasculature and the emergence of apoptosis-resistant cells. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of multiple forms of cell death known to be abundantly expressed in striated muscle. We show for the first time that ARC is expressed in arterial smooth muscle cells of the pulmonary vasculature and is markedly upregulated in several experimental models of PH. In this study, we test the hypothesis that ARC expression is essential for the development of chronic hypoxia-induced PH.
  
  
  RESULTS
  Experiments in which cells or mice were rendered ARC-deficient revealed that ARC not only protected pulmonary arterial smooth muscle cells from hypoxia-induced death, but also facilitated growth factor-induced proliferation and hypertrophy and hypoxia-induced downregulation of selective voltage-gated potassium channels, the latter a hallmark of the syndrome in humans. Moreover, ARC-deficient mice exhibited diminished vascular remodeling, increased apoptosis, and decreased proliferation in response to chronic hypoxia, resulting in marked protection from PH in vivo. Patients with PH have significantly increased ARC expression not only in remodeled vessels but also in the lumen-occluding lesions associated with severe disease.
  
  
  CONCLUSIONS
  These data show that ARC, previously unlinked to pulmonary hypertension, is a critical determinant of vascular remodeling in this syndrome.
authors.affiliation: Johns Hopkins University School of Medicine, Division of Pulmonary and Critical Care Medicine, The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA. mcrow1@jhmi.edu
authors.forename: Ari L
authors.initials: AL
authors.lastname: Zaiman
authors.forename: Rachel
authors.initials: R
authors.lastname: Damico
authors.forename: Alan
authors.initials: A
authors.lastname: Thoms-Chesley
authors.forename: D Clark
authors.initials: DC
authors.lastname: Files
authors.forename: Priya
authors.initials: P
authors.lastname: Kesari
authors.forename: Laura
authors.initials: L
authors.lastname: Johnston
authors.forename: Mara
authors.initials: M
authors.lastname: Swaim
authors.forename: Shehzin
authors.initials: S
authors.lastname: Mozammel
authors.forename: Alan C
authors.initials: AC
authors.lastname: Myers
authors.forename: Marc
authors.initials: M
authors.lastname: Halushka
authors.forename: Hazim
authors.initials: H
authors.lastname: El-Haddad
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Shimoda
authors.forename: Chang-Fu
authors.initials: CF
authors.lastname: Peng
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hassoun
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: Richard N
authors.initials: RN
authors.lastname: Kitsis
authors.forename: Michael T
authors.initials: MT
authors.lastname: Crow
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000502:physiology; D011652:Pulmonary Circulation / Q000502:physiology; D051381:Rats; D015854:Up-Regulation / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D009124:Muscle Proteins; C112246:NOL3 protein, human; C491787:Nol3 protein, mouse; D024642:Potassium Channels, Voltage-Gated
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