G-CSF exerts dual effects on endothelial cells-Opposing actions of direct eNOS induction versus indirect CRP elevation

Kyung Woo Park, Yoo Wook Kwon, Hyun Jai Cho, Jung Im Shin, Yong Jin Kim, Sang Eun Lee, Seock Won Youn, Hyun Chae Lee, Hyun Jae Kang, Philip W. Shaul, Byung Hee Oh, Young Bae Park, Hyo Soo Kim

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Granulocyte-colony stimulating factor (G-CSF) has been shown to have protective effects in the heart and brain. However, it may also be involved in the acute inflammatory response which may be harmful. The effects of G-CSF on endothelial cells (ECs) and the vasculature are mostly unknown. To study the possible dual effects of G-CSF on ECs, we investigated whether G-CSF induces release of C-reactive protein (CRP) by hepatocytes and whether the direct beneficial effects of G-CSF could protect ECs from the detrimental effects of CRP. G-CSF treatment significantly induced monocytes to produce IL-6, and culture supernatants of G-CSF-stimulated monocytes induced CRP production in hepatocytes. On the other hand, G-CSF directly promoted EC proliferation and migration and reversed the deleterious effects of CRP. In mechanistic analyses, G-CSF increased not only the protein expression of endothelial nitric oxide synthase (eNOS), but also its transcription. Furthermore, it enhanced eNOS phosphorylation and activation, leading to increased production of NO. Thus, G-CSF reversed the attenuated production of NO by CRP. These effects of G-CSF on eNOS transcription, translation, and activation were blunted by the PI3K inhibitor, suggesting that EC protective effects of G-CSF were associated with the activation of the Akt/eNOS pathway. In conclusion, although G-CSF induces an inflammatory reaction leading to CRP production, it has direct beneficial effects protecting ECs from the deleterious effects of CRP through activation of Akt/eNOS pathway, leading to an increase in NO production. Our data suggests that G-CSF may exert dual opposing effects on endothelial cells.

Original languageEnglish (US)
Pages (from-to)670-678
Number of pages9
JournalJournal of molecular and cellular cardiology
Volume45
Issue number5
DOIs
StatePublished - Nov 1 2008

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Nitric Oxide Synthase Type III
Granulocyte Colony-Stimulating Factor
C-Reactive Protein
Endothelial Cells
Monocytes
Hepatocytes
Phosphatidylinositol 3-Kinases
Transcriptional Activation
Cell Movement
Interleukin-6

Keywords

  • Akt
  • CRP
  • Endothelial cells
  • Endothelial nitric oxide synthase
  • G-CSF

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

G-CSF exerts dual effects on endothelial cells-Opposing actions of direct eNOS induction versus indirect CRP elevation. / Park, Kyung Woo; Kwon, Yoo Wook; Cho, Hyun Jai; Shin, Jung Im; Kim, Yong Jin; Lee, Sang Eun; Youn, Seock Won; Lee, Hyun Chae; Kang, Hyun Jae; Shaul, Philip W.; Oh, Byung Hee; Park, Young Bae; Kim, Hyo Soo.

In: Journal of molecular and cellular cardiology, Vol. 45, No. 5, 01.11.2008, p. 670-678.

Research output: Contribution to journalArticle

Park, KW, Kwon, YW, Cho, HJ, Shin, JI, Kim, YJ, Lee, SE, Youn, SW, Lee, HC, Kang, HJ, Shaul, PW, Oh, BH, Park, YB & Kim, HS 2008, 'G-CSF exerts dual effects on endothelial cells-Opposing actions of direct eNOS induction versus indirect CRP elevation', Journal of molecular and cellular cardiology, vol. 45, no. 5, pp. 670-678. https://doi.org/10.1016/j.yjmcc.2008.07.002
Park, Kyung Woo ; Kwon, Yoo Wook ; Cho, Hyun Jai ; Shin, Jung Im ; Kim, Yong Jin ; Lee, Sang Eun ; Youn, Seock Won ; Lee, Hyun Chae ; Kang, Hyun Jae ; Shaul, Philip W. ; Oh, Byung Hee ; Park, Young Bae ; Kim, Hyo Soo. / G-CSF exerts dual effects on endothelial cells-Opposing actions of direct eNOS induction versus indirect CRP elevation. In: Journal of molecular and cellular cardiology. 2008 ; Vol. 45, No. 5. pp. 670-678.
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AU - Shin, Jung Im

AU - Kim, Yong Jin

AU - Lee, Sang Eun

AU - Youn, Seock Won

AU - Lee, Hyun Chae

AU - Kang, Hyun Jae

AU - Shaul, Philip W.

AU - Oh, Byung Hee

AU - Park, Young Bae

AU - Kim, Hyo Soo

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AB - Granulocyte-colony stimulating factor (G-CSF) has been shown to have protective effects in the heart and brain. However, it may also be involved in the acute inflammatory response which may be harmful. The effects of G-CSF on endothelial cells (ECs) and the vasculature are mostly unknown. To study the possible dual effects of G-CSF on ECs, we investigated whether G-CSF induces release of C-reactive protein (CRP) by hepatocytes and whether the direct beneficial effects of G-CSF could protect ECs from the detrimental effects of CRP. G-CSF treatment significantly induced monocytes to produce IL-6, and culture supernatants of G-CSF-stimulated monocytes induced CRP production in hepatocytes. On the other hand, G-CSF directly promoted EC proliferation and migration and reversed the deleterious effects of CRP. In mechanistic analyses, G-CSF increased not only the protein expression of endothelial nitric oxide synthase (eNOS), but also its transcription. Furthermore, it enhanced eNOS phosphorylation and activation, leading to increased production of NO. Thus, G-CSF reversed the attenuated production of NO by CRP. These effects of G-CSF on eNOS transcription, translation, and activation were blunted by the PI3K inhibitor, suggesting that EC protective effects of G-CSF were associated with the activation of the Akt/eNOS pathway. In conclusion, although G-CSF induces an inflammatory reaction leading to CRP production, it has direct beneficial effects protecting ECs from the deleterious effects of CRP through activation of Akt/eNOS pathway, leading to an increase in NO production. Our data suggests that G-CSF may exert dual opposing effects on endothelial cells.

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