Document Detail


Endothelial Krüppel-like factor 4 modulates pulmonary arterial hypertension.
MedLine Citation:
PMID:  24156273     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Krüppel-like factor 4 (KLF4) is a transcription factor expressed in the vascular endothelium, where it promotes anti-inflammatory and anticoagulant states, and increases endothelial nitric oxide synthase expression. We examined the role of endothelial KLF4 in pulmonary arterial (PA) hypertension (PAH). Mice with endothelial KLF4 knockdown were exposed to hypoxia for 3 weeks, followed by measurement of right ventricular and PA pressures, pulmonary vascular muscularization, and right ventricular hypertrophy. The effect of KLF4 on target gene expression was assessed in lungs from these mice, verified in vitro by small interfering RNA (siRNA) knockdown of KLF4, and further studied at the promoter level with cotransfection experiments. KLF4 expression was measured in lung tissue from patients with PAH and normal control subjects. We found that, after hypoxia, right ventricular and PA pressures were significantly higher in KLF4 knockdown animals than controls. Knockdown animals also had more severe pulmonary vascular muscularization and right ventricular hypertrophy. KLF4 knockdown resulted in increased pulmonary expression of endothelin-1 and decreased expression of endothelial nitric oxide synthase, endothelin receptor subtype B, and prostacyclin synthase. Concordant findings were observed in vitro, both with siRNA knockdown of KLF4 and promoter activity assays. Finally, KLF4 expression was reduced in lungs from patients with PAH. In conclusion, endothelial KLF4 regulates the transcription of genes involved in key pathways implicated in PAH, and its loss exacerbates pulmonary hypertension in response to chronic hypoxia in mice. These results introduce a novel transcriptional modulator of PAH, with the potential of becoming a new therapeutic target.
Authors:
Mohammad A Shatat; Hongmei Tian; Rongli Zhang; Gaurav Tandon; Andrew Hale; Jason S Fritz; Guangjin Zhou; José Martínez-González; Cristina Rodríguez; Hunter C Champion; Mukesh K Jain; Anne Hamik
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  50     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2014 Mar 
Date Detail:
Created Date:  2014-03-04     Completed Date:  2014-04-24     Revised Date:  2014-10-24    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  647-53     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anoxia / complications
Arterial Pressure*
Case-Control Studies
Cells, Cultured
Cytochrome P-450 Enzyme System / metabolism
Disease Models, Animal
Endothelial Cells / metabolism*
Endothelin-1 / metabolism
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Hypertension, Pulmonary / etiology,  genetics,  metabolism*,  pathology,  physiopathology,  prevention & control
Hypertrophy, Right Ventricular / etiology,  metabolism,  physiopathology
Intramolecular Oxidoreductases / metabolism
Kruppel-Like Transcription Factors / deficiency,  genetics,  metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nitric Oxide Synthase Type III / metabolism
Pulmonary Artery / metabolism*,  pathology,  physiopathology
RNA Interference
Receptor, Endothelin B / metabolism
Time Factors
Transfection
Ventricular Function, Right
Ventricular Pressure
Grant Support
ID/Acronym/Agency:
HL076754/HL/NHLBI NIH HHS; HL086548/HL/NHLBI NIH HHS; HL097593/HL/NHLBI NIH HHS; HL110630/HL/NHLBI NIH HHS; HL1124861/HL/NHLBI NIH HHS; K08HL083090/HL/NHLBI NIH HHS; R01 HL110630/HL/NHLBI NIH HHS; R01 HL119195/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Endothelin-1; 0/GKLF protein; 0/Kruppel-Like Transcription Factors; 0/Receptor, Endothelin B; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, mouse; EC 5.3.-/Intramolecular Oxidoreductases; EC 5.3.99.4/prostacyclin synthetase

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