title: Anti-inflammatory effects of fimasartan via Akt, ERK, and NFκB pathways on astrocytes stimulated by hemolysate.
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.
authors.affiliation: Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
authors.forename: Xiu-Li
authors.initials: XL
authors.lastname: Yang
authors.affiliation: Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.|Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03087, Republic of Korea.
authors.forename: Chi Kyung
authors.initials: CK
authors.lastname: Kim
authors.affiliation: Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
authors.forename: Tae Jung
authors.initials: TJ
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
authors.forename: Doeun
authors.initials: D
authors.lastname: Rim
authors.affiliation: Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
authors.forename: Young-Ju
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Ko
authors.affiliation: Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
authors.forename: Hyunduk
authors.initials: H
authors.lastname: Jang
authors.affiliation: Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. bwyoon@snu.ac.kr.|Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. bwyoon@snu.ac.kr.|Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03087, Republic of Korea. bwyoon@snu.ac.kr.
authors.forename: Byung-Woo
authors.initials: BW
authors.lastname: Yoon
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006470:Hemorrhage; D020672:I-kappa B Proteins / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D000893:Anti-Inflammatory Agents; D001713:Biphenyl Compounds; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D011743:Pyrimidines; D012333:RNA, Messenger; D013777:Tetrazoles; D000072000:NF-KappaB Inhibitor alpha; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C558933:fimasartan
keywords: Astrocyte; Fimasartan; Hemolysate; Inflammation; Intracerebral hemorrhage