Publication

Expression and regulation of HIF-1 alpha in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor

Westra, J., Brouwer, E., van Roosmalen, I. A. M., Doornbos-van der Meer, B., van Leeuwen, M. A., Posthumus, M. D. & Kallenberg, C. G. M., 30-Mar-2010, In : Bmc Musculoskeletal Disorders. 11, 11 p., 61.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Westra, J., Brouwer, E., van Roosmalen, I. A. M., Doornbos-van der Meer, B., van Leeuwen, M. A., Posthumus, M. D., & Kallenberg, C. G. M. (2010). Expression and regulation of HIF-1 alpha in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor. Bmc Musculoskeletal Disorders, 11, [61]. https://doi.org/10.1186/1471-2474-11-61

Author

Westra, Johanna ; Brouwer, Elisabeth ; van Roosmalen, Ingrid A. M. ; Doornbos-van der Meer, Berber ; van Leeuwen, Miek A. ; Posthumus, Marcel D. ; Kallenberg, Cees G. M. / Expression and regulation of HIF-1 alpha in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor. In: Bmc Musculoskeletal Disorders. 2010 ; Vol. 11.

Harvard

Westra, J, Brouwer, E, van Roosmalen, IAM, Doornbos-van der Meer, B, van Leeuwen, MA, Posthumus, MD & Kallenberg, CGM 2010, 'Expression and regulation of HIF-1 alpha in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor', Bmc Musculoskeletal Disorders, vol. 11, 61. https://doi.org/10.1186/1471-2474-11-61

Standard

Expression and regulation of HIF-1 alpha in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor. / Westra, Johanna; Brouwer, Elisabeth; van Roosmalen, Ingrid A. M.; Doornbos-van der Meer, Berber; van Leeuwen, Miek A.; Posthumus, Marcel D.; Kallenberg, Cees G. M.

In: Bmc Musculoskeletal Disorders, Vol. 11, 61, 30.03.2010.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Westra J, Brouwer E, van Roosmalen IAM, Doornbos-van der Meer B, van Leeuwen MA, Posthumus MD et al. Expression and regulation of HIF-1 alpha in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor. Bmc Musculoskeletal Disorders. 2010 Mar 30;11. 61. https://doi.org/10.1186/1471-2474-11-61


BibTeX

@article{cf977b35cc4a4c41b42e32343a7f93e3,
title = "Expression and regulation of HIF-1 alpha in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor",
abstract = "Background: Macrophages expressing the pro-angiogenic transcription factor hypoxia-inducible factor (HIF)-1alpha have been demonstrated in rheumatoid arthritis (RA) in the synovial tissue. Aim of the present study was to investigate intracellular signal transduction regulation of pro-inflammatory HIF-1 alpha expression in macrophages to identify possible new intervention strategies. We investigated the effects of CaMKII-inhibitors amongst other kinase inhibitors, on HIF-1 alpha expression and downstream production of pro-angiogenic factors in macrophages.Methods: Differentiated THP-1 cells and synovial fluid (SF) macrophages were stimulated with 1 mu g/ml LPS with or without pretreatment with specific inhibitors of the ERK pathway (PD98059), the PI3K pathway (LY294002), and the CaMKII pathway (KN93 and SMP-114). mRNA and protein expression of HIF-1 alpha, VEGF, MMP-9, and IL-8 was measured in cell lysates and cell supernatants.Results: HIF-1 alpha protein expression in LPS-stimulated THP-1 macrophages could be blocked by ERK- and PI3K-inhibitors, but also by the CaMKII inhibitor KN93. THP-1 and SF macrophages produced high levels of VEGF, IL-8, and MMP-9, and VEGF protein production was significantly inhibited by PI3K-inhibitor, and by both CaMKII inhibitors. LPS stimulation in an hypoxic environment did not change VEGF levels, suggesting that LPS induced VEGF production in macrophages is more important than the hypoxic induction.Conclusions: Expression of HIF-1 alpha and downstream effects in macrophages are regulated by ERK-, PI3K, but also by CaMKII pathways. Inhibition of HIF-1 alpha protein expression and significant inhibition of VEGF production in macrophages was found using CaMKII inhibitors. This is an unknown but very interesting effect of the CaMKII inhibitor SMP-114, which has been in clinical trial as DMARD for the treatment of RA. This effect may contribute to the anti-arthritic effects of SMP-114.",
keywords = "HYPOXIA-INDUCIBLE FACTOR-1-ALPHA, ENDOTHELIAL GROWTH-FACTOR, RHEUMATOID-ARTHRITIS, SYNOVIAL TISSUE, CELLS, ANGIOGENESIS, HIF-1-ALPHA, ACTIVATION, OXYGEN, RAT",
author = "Johanna Westra and Elisabeth Brouwer and {van Roosmalen}, {Ingrid A. M.} and {Doornbos-van der Meer}, Berber and {van Leeuwen}, {Miek A.} and Posthumus, {Marcel D.} and Kallenberg, {Cees G. M.}",
year = "2010",
month = "3",
day = "30",
doi = "10.1186/1471-2474-11-61",
language = "English",
volume = "11",
journal = "Bmc Musculoskeletal Disorders",
issn = "1471-2474",
publisher = "BioMed Central Ltd.",

}

RIS

TY - JOUR

T1 - Expression and regulation of HIF-1 alpha in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor

AU - Westra, Johanna

AU - Brouwer, Elisabeth

AU - van Roosmalen, Ingrid A. M.

AU - Doornbos-van der Meer, Berber

AU - van Leeuwen, Miek A.

AU - Posthumus, Marcel D.

AU - Kallenberg, Cees G. M.

PY - 2010/3/30

Y1 - 2010/3/30

N2 - Background: Macrophages expressing the pro-angiogenic transcription factor hypoxia-inducible factor (HIF)-1alpha have been demonstrated in rheumatoid arthritis (RA) in the synovial tissue. Aim of the present study was to investigate intracellular signal transduction regulation of pro-inflammatory HIF-1 alpha expression in macrophages to identify possible new intervention strategies. We investigated the effects of CaMKII-inhibitors amongst other kinase inhibitors, on HIF-1 alpha expression and downstream production of pro-angiogenic factors in macrophages.Methods: Differentiated THP-1 cells and synovial fluid (SF) macrophages were stimulated with 1 mu g/ml LPS with or without pretreatment with specific inhibitors of the ERK pathway (PD98059), the PI3K pathway (LY294002), and the CaMKII pathway (KN93 and SMP-114). mRNA and protein expression of HIF-1 alpha, VEGF, MMP-9, and IL-8 was measured in cell lysates and cell supernatants.Results: HIF-1 alpha protein expression in LPS-stimulated THP-1 macrophages could be blocked by ERK- and PI3K-inhibitors, but also by the CaMKII inhibitor KN93. THP-1 and SF macrophages produced high levels of VEGF, IL-8, and MMP-9, and VEGF protein production was significantly inhibited by PI3K-inhibitor, and by both CaMKII inhibitors. LPS stimulation in an hypoxic environment did not change VEGF levels, suggesting that LPS induced VEGF production in macrophages is more important than the hypoxic induction.Conclusions: Expression of HIF-1 alpha and downstream effects in macrophages are regulated by ERK-, PI3K, but also by CaMKII pathways. Inhibition of HIF-1 alpha protein expression and significant inhibition of VEGF production in macrophages was found using CaMKII inhibitors. This is an unknown but very interesting effect of the CaMKII inhibitor SMP-114, which has been in clinical trial as DMARD for the treatment of RA. This effect may contribute to the anti-arthritic effects of SMP-114.

AB - Background: Macrophages expressing the pro-angiogenic transcription factor hypoxia-inducible factor (HIF)-1alpha have been demonstrated in rheumatoid arthritis (RA) in the synovial tissue. Aim of the present study was to investigate intracellular signal transduction regulation of pro-inflammatory HIF-1 alpha expression in macrophages to identify possible new intervention strategies. We investigated the effects of CaMKII-inhibitors amongst other kinase inhibitors, on HIF-1 alpha expression and downstream production of pro-angiogenic factors in macrophages.Methods: Differentiated THP-1 cells and synovial fluid (SF) macrophages were stimulated with 1 mu g/ml LPS with or without pretreatment with specific inhibitors of the ERK pathway (PD98059), the PI3K pathway (LY294002), and the CaMKII pathway (KN93 and SMP-114). mRNA and protein expression of HIF-1 alpha, VEGF, MMP-9, and IL-8 was measured in cell lysates and cell supernatants.Results: HIF-1 alpha protein expression in LPS-stimulated THP-1 macrophages could be blocked by ERK- and PI3K-inhibitors, but also by the CaMKII inhibitor KN93. THP-1 and SF macrophages produced high levels of VEGF, IL-8, and MMP-9, and VEGF protein production was significantly inhibited by PI3K-inhibitor, and by both CaMKII inhibitors. LPS stimulation in an hypoxic environment did not change VEGF levels, suggesting that LPS induced VEGF production in macrophages is more important than the hypoxic induction.Conclusions: Expression of HIF-1 alpha and downstream effects in macrophages are regulated by ERK-, PI3K, but also by CaMKII pathways. Inhibition of HIF-1 alpha protein expression and significant inhibition of VEGF production in macrophages was found using CaMKII inhibitors. This is an unknown but very interesting effect of the CaMKII inhibitor SMP-114, which has been in clinical trial as DMARD for the treatment of RA. This effect may contribute to the anti-arthritic effects of SMP-114.

KW - HYPOXIA-INDUCIBLE FACTOR-1-ALPHA

KW - ENDOTHELIAL GROWTH-FACTOR

KW - RHEUMATOID-ARTHRITIS

KW - SYNOVIAL TISSUE

KW - CELLS

KW - ANGIOGENESIS

KW - HIF-1-ALPHA

KW - ACTIVATION

KW - OXYGEN

KW - RAT

U2 - 10.1186/1471-2474-11-61

DO - 10.1186/1471-2474-11-61

M3 - Article

VL - 11

JO - Bmc Musculoskeletal Disorders

JF - Bmc Musculoskeletal Disorders

SN - 1471-2474

M1 - 61

ER -

ID: 5061544