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dc.contributor.authorSun, Xiaoguang
dc.contributor.authorMathew, Biji
dc.contributor.authorSammani, Saad
dc.contributor.authorJacobson, Jeffrey R.
dc.contributor.authorGarcia, Joe G. N.
dc.date.accessioned2017-06-03T00:57:51Z
dc.date.available2017-06-03T00:57:51Z
dc.date.issued2017-03-21
dc.identifier.citationSimvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells 2017, 7 (1):117 Pulmonary Circulationen
dc.identifier.issn2045-8932
dc.identifier.issn2045-8940
dc.identifier.doi10.1177/2045893217701162
dc.identifier.urihttp://hdl.handle.net/10150/623874
dc.description.abstractWe 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.
dc.description.sponsorshipNational Heart, Lung and Blood Institute [P01HL58064, P01HL98050, P01HL126609]en
dc.language.isoenen
dc.publisherSAGE PUBLICATIONS INCen
dc.relation.urlhttp://journals.sagepub.com/doi/10.1177/2045893217701162en
dc.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.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc/3.0/
dc.subjectsimvastatinen
dc.subjectsphingosine 1-phosphate receptor 1en
dc.subjectpromoter activityen
dc.subjectKruppel-like factor 2en
dc.subjectendotheliumen
dc.subjectacute respiratory distress syndromeen
dc.titleSimvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cellsen
dc.typeArticleen
dc.contributor.departmentUniv Arizona Hlth Sci, Dept Meden
dc.identifier.journalPulmonary Circulationen
dc.description.note12 month embargo; First Published March 21, 2017en
dc.description.collectioninformationThis 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.en
dc.eprint.versionFinal published versionen
refterms.dateFOA2018-03-22T00:00:00Z
html.description.abstractWe 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.


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© 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.
Except where otherwise noted, this item's license is described as © 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.