Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Kwapiszewska, G; Wygrecka, M; Marsh, LM; Schmitt, S; Trösser, R; Wilhelm, J; Helmus, K; Eul, B; Zakrzewicz, A; Ghofrani, HA; Schermuly, RT; Bohle, RM; Grimminger, F; Seeger, W; Eickelberg, O; Fink, L; Weissmann, N.
Fhl-1, a new key protein in pulmonary hypertension.
Circulation. 2008; 118(11): 1183-1194.
Doi: 10.1161/CIRCULATIONAHA.107.761916
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- Führende Autor*innen der Med Uni Graz
- Kwapiszewska-Marsh Grazyna
- Co-Autor*innen der Med Uni Graz
- Marsh Leigh
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- 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. METHODS AND 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Anoxia - complications
- Cell Movement -
- Cell Proliferation -
- Disease Models, Animal -
- Humans -
- Hypertension, Pulmonary - etiology Hypertension, Pulmonary - pathology
- Intracellular Signaling Peptides and Proteins - analysis Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - physiology
- LIM Domain Proteins -
- Lung - chemistry Lung - metabolism
- Mice -
- Muscle Proteins - analysis Muscle Proteins - genetics Muscle Proteins - physiology
- Muscle, Smooth -
- Proteomics - methods
- Pulmonary Artery -
- RNA, Small Interfering - pharmacology
- Up-Regulation -
- Find related publications in this database (Keywords)
- hypertension, pulmonary
- hypoxia
- remodeling
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