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Simvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells
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 Krüppel-like factor 2 (KLF2) serves as a critical regulator for c...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448536/ https://www.ncbi.nlm.nih.gov/pubmed/28680571 http://dx.doi.org/10.1177/2045893217701162 |
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author | Sun, Xiaoguang Mathew, Biji Sammani, Saad Jacobson, Jeffrey R. Garcia, Joe G. N. |
author_facet | Sun, Xiaoguang Mathew, Biji Sammani, Saad Jacobson, Jeffrey R. Garcia, Joe G. N. |
author_sort | Sun, Xiaoguang |
collection | PubMed |
description | 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 Krüppel-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 μM), 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. |
format | Online Article Text |
id | pubmed-5448536 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-54485362017-06-08 Simvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells Sun, Xiaoguang Mathew, Biji Sammani, Saad Jacobson, Jeffrey R. Garcia, Joe G. N. Pulm Circ Research Articles 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 Krüppel-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 μM), 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. SAGE Publications 2017-03-21 /pmc/articles/PMC5448536/ /pubmed/28680571 http://dx.doi.org/10.1177/2045893217701162 Text en © 2017 by Pulmonary Vascular Research Institute http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Research Articles Sun, Xiaoguang Mathew, Biji Sammani, Saad Jacobson, Jeffrey R. Garcia, Joe G. N. Simvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells |
title | Simvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells |
title_full | Simvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells |
title_fullStr | Simvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells |
title_full_unstemmed | Simvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells |
title_short | Simvastatin-induced sphingosine 1−phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells |
title_sort | simvastatin-induced sphingosine 1−phosphate receptor 1 expression is klf2-dependent in human lung endothelial cells |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448536/ https://www.ncbi.nlm.nih.gov/pubmed/28680571 http://dx.doi.org/10.1177/2045893217701162 |
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