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Inflammation Research

, Volume 65, Issue 2, pp 115–123 | Cite as

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 YoonEmail author
Original Research Paper

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.

Keywords

Fimasartan Hemolysate Intracerebral hemorrhage Inflammation Astrocyte 

Notes

Acknowledgments

This work was supported by grant from the Boryung Pharmaceutical Company (800-20150256), and the Health Fellowship Foundation (2014-810115), Seoul, Republic of Korea. The research was also supported by a grant of the Korean Health Technology R&D Project funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1277). The funding organization had no role in the design, conduct, or analysis conducted during this study, or in the preparation of this report.

Compliance with ethical standards

Disclosure

The authors have nothing to disclose.

Supplementary material

11_2015_895_MOESM1_ESM.docx (366 kb)
Supplementary material 1 (DOCX 365 kb)

References

  1. 1.
    Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009;373:1632–44.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Lee ST, Chu K, Sinn DI, Jung KH, Kim EH, Kim SJ, et al. Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage. J Neurochem. 2006;96:1728–39.PubMedCrossRefGoogle Scholar
  3. 3.
    Hong K-S, Bang OY, Kang D-W, Yu K-H, Bae H-J, Lee JS, et al. Stroke statistics in Korea: part I. Epidemiology and risk factors: a report from the korean stroke society and clinical research center for stroke. J Stroke. 2013;15:2–20.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Lu A, Tang Y, Ran R, Ardizzone TL, Wagner KR, Sharp FR. Brain genomics of intracerebral hemorrhage. J Cereb Blood Flow Metab. 2006;26:230–52.PubMedCrossRefGoogle Scholar
  5. 5.
    Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5:53–63.PubMedCrossRefGoogle Scholar
  6. 6.
    Sasaki T, Kasuya H, Onda H, Sasahara A, Goto S, Hori T, et al. Role of p38 mitogen-activated protein kinase on cerebral vasospasm after subarachnoid hemorrhage. Stroke. 2004;35:1466–70.PubMedCrossRefGoogle Scholar
  7. 7.
    Xi G, Hua Y, Bhasin RR, Ennis SR, Keep RF, Hoff JT. Mechanisms of edema formation after intracerebral hemorrhage effects of extravasated red blood cells on blood flow and blood-brain barrier integrity. Stroke. 2001;32:2932–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Gong C, Boulis N, Qian J, Turner DE, Hoff JT, Keep RF. Intracerebral hemorrhage-induced neuronal death. Neurosurgery. 2001;48:875–82 (discussion 882–3).PubMedGoogle Scholar
  9. 9.
    Lu H, Shi J-X, Zhang D-M, Shen J, Lin Y-X, Hang C-H, et al. Hemolysate-induced expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 expression in cultured brain microvascular endothelial cells via through ros-dependent nf-κb pathways. Cell Mol Neurobiol. 2009;29:87–95.PubMedCrossRefGoogle Scholar
  10. 10.
    Edye ME, Lopez-Castejon G, Allan SM, Brough D. Acidosis drives damage-associated molecular pattern (DAMP)-induced interleukin-1 secretion via a caspase-1-independent pathway. J Biol Chem. 2013;288:30485–94.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Lu H, Shi JX, Zhang DM, Wang HD, Hang CH, Chen HL, et al. Inhibition of hemolysate-induced iNOS and COX-2 expression by genistein through suppression of NF-small ka, CyrillicB activation in primary astrocytes. J Neurol Sci. 2009;278:91–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Lu H, Shi J-X, Zhang D-M, Chen H-L, Qi M, Yin H-X. Genistein, a soybean isoflavone, reduces the production of pro-inflammatory and adhesion molecules induced by hemolysate in brain microvascular endothelial cells. Acta Neurol Belg. 2009;109:32.PubMedGoogle Scholar
  13. 13.
    Zanchetti A, Elmfeldt D. Findings and implications of the study on cognition and prognosis in the elderly (SCOPE)–a review. Blood Press. 2006;15:71–9.PubMedCrossRefGoogle Scholar
  14. 14.
    McFarlane SI. Role of angiotensin receptor blockers in diabetes: implications of recent clinical trials. Expert Rev Cardiovasc Ther. 2009;7:1363–71.PubMedCrossRefGoogle Scholar
  15. 15.
    Ismail H, Mitchell R, McFarlane SI, Makaryus AN. Pleiotropic effects of inhibitors of the RAAS in the diabetic population: above and beyond blood pressure lowering. Curr Diabetes Rep. 2010;10:32–6.CrossRefGoogle Scholar
  16. 16.
    Benicky J, Sánchez-Lemus E, Honda M, Pang T, Orecna M, Wang J, et al. Angiotensin II AT1 receptor blockade ameliorates brain inflammation. Neuropsychopharmacology. 2011;36:857–70.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Lou M, Blume A, Zhao Y, Gohlke P, Deuschl G, Herdegen T, et al. Sustained blockade of brain AT1 receptors before and after focal cerebral ischemia alleviates neurologic deficits and reduces neuronal injury, apoptosis, and inflammatory responses in the rat. J Cereb Blood Flow Metab. 2004;24:536–47.PubMedCrossRefGoogle Scholar
  18. 18.
    Faure S, Oudart N, Javellaud J, Fournier A, Warnock DG, Achard J-M. Synergistic protective effects of erythropoietin and olmesartan on ischemic stroke survival and post-stroke memory dysfunctions in the gerbil. J Hypertens. 2006;24:2255–61.PubMedCrossRefGoogle Scholar
  19. 19.
    Saavedra JM, Angiotensin II. AT1 receptor blockers as treatments for inflammatory brain disorders. Clin Sci Lond. 2012;123:567–90.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Villapol S, Saavedra JM. Neuroprotective effects of angiotensin receptor blockers. Am J Hypertens. 2015;28:289–99.PubMedCrossRefGoogle Scholar
  21. 21.
    Sanchez-Lemus E, Murakami Y, Larrayoz-Roldan IM, Moughamian AJ, Pavel J, Nishioku T, et al. Angiotensin II AT1 receptor blockade decreases lipopolysaccharide-induced inflammation in the rat adrenal gland. Endocrinology. 2008;149:5177–88.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kono S, Kurata T, Sato K, Omote Y, Hishikawa N, Yamashita T, et al. Neurovascular protection by telmisartan via reducing neuroinflammation in stroke-resistant spontaneously hypertensive rat brain after ischemic stroke. J Stroke Cerebrovasc Dis. 2015;24:537–47.PubMedCrossRefGoogle Scholar
  23. 23.
    Jung K-H, Chu K, Lee S-T, Kim S-J, Song E-C, Kim E-H, et al. Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. J Pharmacol Exp Ther. 2007;322:1051–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Kim JH, Lee JH, Paik SH, Kim JH, Chi YH. Fimasartan, a novel angiotensin II receptor antagonist. Arch Pharm Res. 2012;35:1123–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Han J, Park SJ, Thu VT, Lee SR, le Long T, Kim HK, et al. Effects of the novel angiotensin II receptor type I antagonist, fimasartan on myocardial ischemia/reperfusion injury. Int J Cardiol. 2013;168:2851–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Kim CK, Yang X-L, Kim Y-J, Choi I-Y, Jeong H-G, Park H-K, et al. Effect of long-term treatment with fimasartan on transient focal ischemia in rat brain. Biomed Res Int. 2015;2015:295925. doi: 10.1155/2015/295925.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Savoia C, Schiffrin EL. Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clin Sci Lond. 2007;112:375–84.PubMedCrossRefGoogle Scholar
  28. 28.
    Aoki T, Takenaka K, Suzuki S, Kassell NF, Sagher O, Lee KS. The role of hemolysate in the facilitation of oxyhemoglobin-induced contraction in rabbit basilar arteries. J Neurosurg. 1994;81:261–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Fann DY, Santro T, Manzanero S, Widiapradja A, Cheng YL, Lee SY, et al. Intermittent fasting attenuates inflammasome activity in ischemic stroke. Exp Neurol. 2014;257:114–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Deroide N, Li X, Lerouet D, Van Vré E, Baker L, Harrison J, et al. MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury. J Clin Invest. 2013;123:1176.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Wagner KR, Sharp FR, Ardizzone TD, Lu A, Clark JF. Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab. 2003;23:629–52.PubMedCrossRefGoogle Scholar
  32. 32.
    Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke. 2011;42:1781–6.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Benicky J, Sanchez-Lemus E, Pavel J, Saavedra JM. Anti-inflammatory effects of angiotensin receptor blockers in the brain and the periphery. Cell Mol Neurobiol. 2009;29:781–92.PubMedCrossRefGoogle Scholar
  34. 34.
    Michel MC, Foster C, Brunner HR, Liu L. A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists. Pharmacol Rev. 2013;65:809–48.PubMedCrossRefGoogle Scholar
  35. 35.
    Shimizu K, Takashima T, Yamane T, Sasaki M, Kageyama H, Hashizume Y, et al. Whole-body distribution and radiation dosimetry of [11C] telmisartan as a biomarker for hepatic organic anion transporting polypeptide (OATP) 1B3. Nucl Med Biol. 2012;39:847–53.PubMedCrossRefGoogle Scholar
  36. 36.
    Noda A, Fushiki H, Murakami Y, Sasaki H, Miyoshi S, Kakuta H, et al. Brain penetration of telmisartan, a unique centrally acting angiotensin II type 1 receptor blocker, studied by PET in conscious rhesus macaques. Nucl Med Biol. 2012;39:1232–5.PubMedCrossRefGoogle Scholar
  37. 37.
    Dong Y, Benveniste EN. Immune function of astrocytes. Glia. 2001;36:180–90.PubMedCrossRefGoogle Scholar
  38. 38.
    Lanz TV, Ding Z, Ho PP, Luo J, Agrawal AN, Srinagesh H, et al. Angiotensin II sustains brain inflammation in mice via TGF-β. J Clin Invest. 2010;120:2782.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Saavedra JM. Brain and pituitary angiotensin. Endocr Rev. 1992;13:329–80.PubMedCrossRefGoogle Scholar
  40. 40.
    Trendelenburg G. Molecular regulation of cell fate in cerebral ischemia: role of the inflammasome and connected pathways. J Cereb Blood Flow Metab. 2014;34:1857–67.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 2007;28:138–45.PubMedCrossRefGoogle Scholar
  42. 42.
    Tuppo EE, Arias HR. The role of inflammation in Alzheimer’s disease. Int J Biochem Cell. 2005;37:289–305.CrossRefGoogle Scholar
  43. 43.
    Zhao Y, Rempe DA. Targeting astrocytes for stroke therapy. Neurotherapeutics. 2010;7:439–51.PubMedCrossRefGoogle Scholar
  44. 44.
    Chen JH, Chuang SY, Chen HJ, Yeh WT, Pan WH. Serum uric acid level as an independent risk factor for all-cause, cardiovascular, and ischemic stroke mortality: a chinese cohort study. Arthritis Rheum. 2009;61:225–32.PubMedCrossRefGoogle Scholar
  45. 45.
    Shih VF-S, Tsui R, Caldwell A, Hoffmann A. A single NFκB system for both canonical and non-canonical signaling. Cell Res. 2011;21:86–102.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Novack DV. Role of NF-κB in the skeleton. Cell Res. 2011;21:169–82.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Xu C, Shen G, Chen C, Gélinas C. Kong A-NT. Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IκBα, IKK pathway in human prostate cancer PC-3 cells. Oncogene. 2005;24:4486–95.PubMedCrossRefGoogle Scholar
  48. 48.
    O’Neill LA, Kaltschmidt C. NF-kappa B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci. 1997;20:252–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Ryu S, Shin JS, Cho YW, Kim HK, Paik SH, Lee JH, et al. Fimasartan, anti-hypertension drug, suppressed inducible nitric oxide synthase expressions via nuclear factor-kappa B and activator protein-1 inactivation. Biol Pharm Bull. 2013;36:467–74.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing 2015

Authors and Affiliations

  • Xiu-Li Yang
    • 1
    • 2
  • Chi Kyung Kim
    • 1
    • 2
    • 3
  • Tae Jung Kim
    • 1
    • 2
  • Jing Sun
    • 2
  • Doeun Rim
    • 1
  • Young-Ju Kim
    • 1
    • 2
  • Sang-Bae Ko
    • 1
    • 2
  • Hyunduk Jang
    • 1
    • 2
  • Byung-Woo Yoon
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of NeurologySeoul National University HospitalSeoulRepublic of Korea
  2. 2.Biomedical Research InstituteSeoul National University HospitalSeoulRepublic of Korea
  3. 3.Neuroscience Research InstituteSeoul National University College of MedicineSeoulRepublic of Korea

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