title: Classical transient receptor potential channel 1 in hypoxia-induced pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is a life-threatening disease, characterized by pulmonary vascular remodeling. Abnormal smooth muscle cell proliferation is a primary hallmark of chronic hypoxia-induced PH. Essential for cell growth are alterations in the intracellular Ca(2+) homeostasis. Classical transient receptor potential (TRPC) proteins have been suggested to contribute to PH development, as TRPC1 and TRPC6 are predominantly expressed in precapillary pulmonary arterial smooth muscle cells (PASMC). Studies in a TRPC6-deficient mouse model revealed an essential function of TRPC6 in acute but not in chronic hypoxia.
  
  
  OBJECTIVE
  We aimed to identify the importance of TRPC1 in the pathogenesis of chronic hypoxia-induced PH in mice.
  
  
  METHODS
  TRPC1 expression analysis was performed using real-time polymerase chain reaction. TRPC1 function was assessed by in vivo experiments in TRPC1(-/-) animals as well as in isolated precapillary murine PASMC after TRPC1 knockdown by TRPC1-specific small interfering RNAs.
  
  
  RESULTS
  Only TRPC1 mRNA was up-regulated under hypoxia in isolated murine PASMC (1% O2 for 72 h). Hypoxia-induced proliferation of murine PASMC was attenuated in cells treated with small interfering RNA against TRPC1 and in cells isolated from TRPC1(-/-) animals compared with untreated and wild-type cells. TRPC1(-/-) mice did not develop PH in response to chronic hypoxia (FI(O2) 0.10 for 21 d) and had less vascular muscularization but a similar degree of right ventricular hypertrophy compared with wild-type mice.
  
  
  CONCLUSIONS
  Our results indicate an important role of TRPC1 in pulmonary vascular remodeling underlying the development of hypoxia-induced PH.
authors.affiliation: 1 Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Malczyk
authors.forename: Christine
authors.initials: C
authors.lastname: Veith
authors.forename: Beate
authors.initials: B
authors.lastname: Fuchs
authors.forename: Katharina
authors.initials: K
authors.lastname: Hofmann
authors.forename: Ursula
authors.initials: U
authors.lastname: Storch
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.forename: Katrin
authors.initials: K
authors.lastname: Ahlbrecht
authors.forename: Claudia
authors.initials: C
authors.lastname: Fecher-Trost
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000150:complications*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D050052:TRPC Cation Channels / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1