Anti-inflammatory effects of fimasartan via Akt, ERK, and NFκB pathways on astrocytes stimulated by hemolysate

Xiu Li Yang, Chi Kyung Kim, Tae Jung Kim, Jing Sun, Doeun Rim, Young Ju Kim, Sang Bae Ko, Hyunduk Jang, Byung Woo Yoon

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Objective: The aim of this study was to investigate whether fimasartan, a novel angiotensin II receptor blocker, modulates hemolysate-induced inflammation in astrocytes. Methods: We stimulated astrocytes with hemolysate to induce hemorrhagic inflammation in vitro. Astrocytes were pretreated with fimasartan and then incubated with hemolysate at different durations. Anti-inflammatory cell signaling molecules including Akt, extracellular signal regulated kinase (ERK), NFκB and cyclooxygenase-2 (COX-2) were assessed by western blotting. Pro-inflammatory mediators were evaluated by real-time RT-PCR and ELISA. Results: The stimulation by hemolysate generated a robust activation of inflammatory signaling pathways in astrocytes. Hemolysate increased the phosphorylation of Akt at 1 h, and ERK1/2 at 20 min compared with the control group and promoted the degradation of IκBα. Pretreated fimasartan significantly decreased hemolysate-induced phosphorylation of Akt and ERK1/2. In addition, fimasartan also suppressed NFκB-related inflammatory pathways induced by hemolysate, including reduction of the gene expression of NFκB, and decreased nuclear translocation of NFκB and degradation of IκB. This reduction of inflammatory upstream pathways decreased the expression of inflammatory end-products: COX-2 and interleukin-1 (IL-1β). Furthermore, the expression of COX-2 was attenuated by both Akt inhibitor (LY294002) and ERK inhibitor (U0126), and IκBα degradation was suppressed by LY294002. Conclusions: These results demonstrate that pretreatment with fimasartan to astrocytes suppresses the inflammatory responses induced by hemolysate. Akt, ERK and NFκB were associated with hemolysate-induced COX-2 and IL-1β expression. Based on these mechanisms, fimasartan could be a candidate anti-inflammatory regulator for the treatment of intracerebral hemorrhage.

Original languageEnglish
Pages (from-to)115-123
Number of pages9
JournalInflammation Research
Volume65
Issue number2
DOIs
Publication statusPublished - 2016 Feb 1
Externally publishedYes

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Extracellular Signal-Regulated MAP Kinases
Astrocytes
Anti-Inflammatory Agents
Cyclooxygenase 2
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Interleukin-1
Phosphorylation
Inflammation
Angiotensin Receptor Antagonists
Cerebral Hemorrhage
fimasartan
Real-Time Polymerase Chain Reaction
Western Blotting
Enzyme-Linked Immunosorbent Assay
Gene Expression
Control Groups

Keywords

  • Astrocyte
  • Fimasartan
  • Hemolysate
  • Inflammation
  • Intracerebral hemorrhage

ASJC Scopus subject areas

  • Immunology
  • Pharmacology

Cite this

Anti-inflammatory effects of fimasartan via Akt, ERK, and NFκB pathways on astrocytes stimulated by hemolysate. / Yang, Xiu Li; Kim, Chi Kyung; Kim, Tae Jung; Sun, Jing; Rim, Doeun; Kim, Young Ju; Ko, Sang Bae; Jang, Hyunduk; Yoon, Byung Woo.

In: Inflammation Research, Vol. 65, No. 2, 01.02.2016, p. 115-123.

Research output: Contribution to journalArticle

Yang, Xiu Li ; Kim, Chi Kyung ; Kim, Tae Jung ; Sun, Jing ; Rim, Doeun ; Kim, Young Ju ; Ko, Sang Bae ; Jang, Hyunduk ; Yoon, Byung Woo. / Anti-inflammatory effects of fimasartan via Akt, ERK, and NFκB pathways on astrocytes stimulated by hemolysate. In: Inflammation Research. 2016 ; Vol. 65, No. 2. pp. 115-123.
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AU - Yang, Xiu Li

AU - Kim, Chi Kyung

AU - Kim, Tae Jung

AU - Sun, Jing

AU - Rim, Doeun

AU - Kim, Young Ju

AU - Ko, Sang Bae

AU - Jang, Hyunduk

AU - Yoon, Byung Woo

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AB - Objective: The aim of this study was to investigate whether fimasartan, a novel angiotensin II receptor blocker, modulates hemolysate-induced inflammation in astrocytes. Methods: We stimulated astrocytes with hemolysate to induce hemorrhagic inflammation in vitro. Astrocytes were pretreated with fimasartan and then incubated with hemolysate at different durations. Anti-inflammatory cell signaling molecules including Akt, extracellular signal regulated kinase (ERK), NFκB and cyclooxygenase-2 (COX-2) were assessed by western blotting. Pro-inflammatory mediators were evaluated by real-time RT-PCR and ELISA. Results: The stimulation by hemolysate generated a robust activation of inflammatory signaling pathways in astrocytes. Hemolysate increased the phosphorylation of Akt at 1 h, and ERK1/2 at 20 min compared with the control group and promoted the degradation of IκBα. Pretreated fimasartan significantly decreased hemolysate-induced phosphorylation of Akt and ERK1/2. In addition, fimasartan also suppressed NFκB-related inflammatory pathways induced by hemolysate, including reduction of the gene expression of NFκB, and decreased nuclear translocation of NFκB and degradation of IκB. This reduction of inflammatory upstream pathways decreased the expression of inflammatory end-products: COX-2 and interleukin-1 (IL-1β). Furthermore, the expression of COX-2 was attenuated by both Akt inhibitor (LY294002) and ERK inhibitor (U0126), and IκBα degradation was suppressed by LY294002. Conclusions: These results demonstrate that pretreatment with fimasartan to astrocytes suppresses the inflammatory responses induced by hemolysate. Akt, ERK and NFκB were associated with hemolysate-induced COX-2 and IL-1β expression. Based on these mechanisms, fimasartan could be a candidate anti-inflammatory regulator for the treatment of intracerebral hemorrhage.

KW - Astrocyte

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KW - Inflammation

KW - Intracerebral hemorrhage

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