title: Fhl-1, a new key protein in pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is a severe disease with a poor prognosis. Different forms of PH are characterized by pronounced vascular remodeling, resulting in increased vascular resistance and subsequent right heart failure. The molecular pathways triggering the remodeling process are poorly understood. We hypothesized that underlying key factors can be identified at the onset of the disease. Thus, we screened for alterations to protein expression in lung tissue at the onset of PH in a mouse model of hypoxia-induced PH.
  
  
  RESULTS
  Using 2-dimensional polyacrylamide gel electrophoresis in combination with matrix-assisted laser desorption/ionization time-of-flight analysis, we identified 36 proteins that exhibited significantly altered expression after short-term hypoxic exposure. Among these, Fhl-1, which is known to be involved in muscle development, was one of the most prominently upregulated proteins. Further analysis by immunohistochemistry, Western blot, and laser-assisted microdissection followed by quantitative polymerase chain reaction confirmed the upregulation of Fhl-1, particularly in the pulmonary vasculature. Comparable upregulation was confirmed (1) after full establishment of hypoxia-induced PH, (2) in 2 rat models of PH (monocrotaline-treated and hypoxic rats treated with the vascular endothelial growth factor receptor antagonist SU5416), and (3) in lungs from patients with idiopathic pulmonary arterial hypertension. Furthermore, we demonstrated that regulation of Fhl-1 was hypoxia-inducible transcription factor dependent. Abrogation of Fhl-1 expression in primary human pulmonary artery smooth muscle cells by small-interfering RNA suppressed, whereas Fhl-1 overexpression increased, migration and proliferation. Coimmunoprecipitation experiments identified Talin1 as a new interacting partner of Fhl-1.
  
  
  CONCLUSIONS
  Protein screening identified Fhl-1 as a novel protein regulated in various forms of PH, including idiopathic pulmonary arterial hypertension.
authors: Med Klinik II, University of Giessen Lung Center, Klinik Strasse 36, 35392 Giessen, Germany. Grazyna.Kwapiszewska@uglc.de
authors: Grazyna
authors: G
authors: Kwapiszewska
authors: Malgorzata
authors: M
authors: Wygrecka
authors: Leigh M
authors: LM
authors: Marsh
authors: Sigrid
authors: S
authors: Schmitt
authors: Roger
authors: R
authors: Trösser
authors: Jochen
authors: J
authors: Wilhelm
authors: Katja
authors: K
authors: Helmus
authors: Bastian
authors: B
authors: Eul
authors: Anna
authors: A
authors: Zakrzewicz
authors: Hossein A
authors: HA
authors: Ghofrani
authors: Ralph T
authors: RT
authors: Schermuly
authors: Rainer M
authors: RM
authors: Bohle
authors: Friedrich
authors: F
authors: Grimminger
authors: Werner
authors: W
authors: Seeger
authors: Oliver
authors: O
authors: Eickelberg
authors: Ludger
authors: L
authors: Fink
authors: Norbert
authors: N
authors: Weissmann
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000473:pathology; D000860:Hypoxia / Q000150:complications; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology; D060588:LIM Domain Proteins; D008168:Lung / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D009124:Muscle Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D009130:Muscle, Smooth; D040901:Proteomics / Q000379:methods; D011651:Pulmonary Artery; D034741:RNA, Small Interfering / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C101149:FHL1 protein, human; C486306:Fhl1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D034741:RNA, Small Interfering