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    Simvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells

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    Author
    Sun, Xiaoguang
    Mathew, Biji
    Sammani, Saad
    Jacobson, Jeffrey R.
    Garcia, Joe G. N.
    Affiliation
    Univ Arizona Hlth Sci, Dept Med
    Issue Date
    2017-03-21
    Keywords
    simvastatin
    sphingosine 1-phosphate receptor 1
    promoter activity
    Kruppel-like factor 2
    endothelium
    acute respiratory distress syndrome
    
    Metadata
    Show full item record
    Publisher
    SAGE PUBLICATIONS INC
    Citation
    Simvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells 2017, 7 (1):117 Pulmonary Circulation
    Journal
    Pulmonary Circulation
    Rights
    © 2017 by Pulmonary Vascular Research Institute. Creative Commons Non Commercial CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    We have demonstrated that simvastatin and sphingosine 1-phosphate (S1P) both attenuate increased vascular permeability in preclinical models of acute respiratory distress syndrome. However, the underlying mechanisms remain unclear. As Kruppel-like factor 2 (KLF2) serves as a critical regulator for cellular stress response in endothelial cells (EC), we hypothesized that simvastatin enhances endothelial barrier function via increasing expression of the barrier-promoting S1P receptor, S1PR1, via a KLF2-dependent mechanism. S1PR1 luciferase reporter promoter activity in human lung artery EC (HPAEC) was tested after simvastatin (5 mu M), and S1PR1 and KLF2 protein expression detected by immunoblotting. In vivo, transcription and expression of S1PR1 and KLF2 in mice lungs were detected by microarray profiling and immunoblotting after exposure to simvastatin (10 mg/kg). Endothelial barrier function was measured by trans-endothelial electrical resistance with the S1PR1 agonist FTY720-(S)-phosphonate. Both S1PR1 and KLF2 gene expression (mRNA, protein) were significantly increased by simvastatin in vitro and in vivo. S1PR1 promoter activity was significantly increased by simvastatin (P < 0.05), which was significantly attenuated by KLF2 silencing (siRNA). Simvastatin induced KLF2 recruitment to the S1PR1 promoter, and consequently, significantly augmented the effects of the S1PR1 agonist on EC barrier enhancement (P < 0.05), which was significantly attenuated by KLF2 silencing (P < 0.05). These results suggest that simvastatin upregulates S1PR1 transcription and expression via the transcription factor KLF2, and consequently augments the effects of S1PR1 agonists on preserving vascular barrier integrity. These results may lead to novel combinatorial therapeutic strategies for lung inflammatory syndromes.
    Note
    12 month embargo; First Published March 21, 2017
    ISSN
    2045-8932
    2045-8940
    DOI
    10.1177/2045893217701162
    Version
    Final published version
    Sponsors
    National Heart, Lung and Blood Institute [P01HL58064, P01HL98050, P01HL126609]
    Additional Links
    http://journals.sagepub.com/doi/10.1177/2045893217701162
    ae974a485f413a2113503eed53cd6c53
    10.1177/2045893217701162
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