Systemic and cerebral vascular endothelial growth factor levels increase in murine cerebral malaria along with increased calpain and caspase activity and can be reduced by erythropoietin treatment

Frontiers in Immunology

Volumn 5, Issue JUN, 2014, Pages

  Hempel, Casper ^a,b   Hoyer, Nils ^a,b   Kildemoes, Anna ^a,b   Jendresen, Charlotte Bille ^a,b   Kurtzhals, Jørgen Anders Lindholm ^a,b  

^a Centre for Medical Parasitology Department of Clinical Microbiology Copenhagen University Hospital ^*  (Denmark)

^b UNIVERSITY OF COPENHAGEN   (Denmark)

Author keywords

Brain; Cerebral malaria; Erythropoietin; Hypoxia; Inflammation; Neuropathology; VEGF

Indexed keywords

EID: 84905649353     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2014.00291     Document Type: Article

References (64)

1. Hay SI, Okiro EA, Gething PW, Patil AP, Tatem AJ, Guerra CA, et al. Estimating the global clinical burden of Plasmodium falciparum malaria in 2007. PLoS Med (2010) 7:e1000290. doi: 10.1371/journal.pmed.1000290
2. van der Heyde HC, Nolan J, Combes V, Gramaglia I, Grau GE. A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol (2006) 22:503-8. doi:10.1016/j.pt.2006.09.002
3. Warrell DA, White NJ, Veall N, Looareesuwan S, Chanthavanich P, Phillips RE, et al. Cerebral anaerobic glycolysis and reduced cerebral oxygen transport in human cerebral malaria. Lancet (1988) 2:534-8. doi:10.1016/S0140-6736(88)92658-X
4. Penet MF, Viola A, Confort-Gouny S, Le FY, Duhamel G, Kober F, et al. Imaging experimental cerebral malaria in vivo: significant role of ischemic brain edema. J Neurosci (2005) 25:7352-8. doi:10.1523/JNEUROSCI.1002-05.2005
5. Hempel C, Combes V, Hunt NH, Lindholm Kurtzhals JA, Raymond Grau GE. CNS hypoxia is more pronounced in murine cerebral than noncerebral malaria and reversed by erythropoietin. Am J Pathol (2011) 179:1939-50. doi:10.1016/j.ajpath.2011.06.027
6. Beare NA, Harding SP, Taylor TE, Lewallen S, Molyneux ME. Perfusion abnormalities in children with cerebral malaria and malarial retinopathy. J Infect Dis (2009) 199:263-71. doi:10.1086/595735
7. Maiese K, Chong ZZ, Li F, Shang YC. Erythropoietin: elucidating new cellular targets that broaden therapeutic strategies. Prog Neurobiol (2008) 85:194-213. doi:10.1016/j.pneurobio.2008.02.002
8. Ratcliffe PJ. HIF-1 and HIF-2: working alone or together in hypoxia? J Clin Invest (2007) 117:862-5. doi:10.1172/JCI31750
9. Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol (2002) 64:993-8. doi:10.1016/S0006-2952(02)01168-1
10. Skuli N, Majmundar AJ, Krock BL, Mesquita RC, Mathew LK, Quinn ZL, et al. Endothelial HIF-2alpha regulates murine pathological angiogenesis and revascularization processes. J Clin Invest (2012) 122:1427-43. doi:10.1172/JCI57322
11. Warnecke C, Zaborowska Z, Kurreck J, Erdmann VA, Frei U, Wiesener M, et al. Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. FASEB J (2004) 18:1462-4. doi:10.1096/fj.04-1640fje
12. Ghezzi P, Brines M. Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ (2004) 11(Suppl 1):S37-44. doi:10.1038/sj.cdd.4401450
13. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A (2000) 97:10526-31. doi:10.1073/pnas.97.19.10526
14. Wiese L, Hempel C, Penkowa M, Kirkby N, Kurtzhals JA. Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria. Malar J (2008) 7:3. doi:10.1186/1475-2875-7-3
15. Kaiser K, Texier A, Ferrandiz J, Buguet A, Meiller A, Latour C, et al. Recombinant human erythropoietin prevents the death of mice during cerebral malaria. J Infect Dis (2006) 193:987-95. doi:10.1086/500844
16. Bienvenu AL, Ferrandiz J, Kaiser K, Latour C, Picot S. Artesunate-erythropoietin combination for murine cerebral malaria treatment. Acta Trop (2008) 106(2):104-8. doi:10.1016/j.actatropica.2008.02.001
17. Picot S, Bienvenu AL, Konate S, Sissoko S, Barri A, Diarra E, et al. Safety of epoietin beta-quinine drug combination in children with cerebral malaria in Mali. Malar J (2009) 8:169. doi:10.1186/1475-2875-8-169
18. Fong GH. Regulation of angiogenesis by oxygen sensing mechanisms. J Mol Med (2009) 87:549-60. doi:10.1007/s00109-009-0458-z
19. Zhong XS, Zheng JZ, Reed E, Jiang BH. SU5416 inhibited VEGF and HIF-1alpha expression through the PI3K/AKT/p70S6K1 signaling pathway. Biochem Biophys Res Commun (2004) 324:471-80. doi:10.1016/j.bbrc.2004.09.082
20. Brekken RA, Huang X, King SW, Thorpe PE. Vascular endothelial growth factor as a marker of tumor endothelium. Cancer Res (1998) 58:1952-9.
21. Lee HS, Han J, Bai HJ, Kim KW. Brain angiogenesis in developmental and pathological processes: regulation, molecular and cellular communication at the neurovascular interface. FEBS J (2009) 276:4622-35. doi:10.1111/j.1742-4658.2009.07174.x
22. Deininger MH, Winkler S, Kremsner PG, Meyermann R, Schluesener HJ. Angiogenic proteins in brains of patients who died with cerebral malaria. J Neuroimmunol (2003) 142:101-11. doi:10.1016/S0165-5728(03)00250-9
23. Casals-Pascual C, Idro R, Gicheru N, Gwer S, Kitsao B, Gitau E, et al. High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral malaria. Proc Natl Acad Sci U S A (2008) 105:2634-9. doi:10.1073/pnas.0709715105
24. Jain V, Armah HB, Tongren JE, Ned RM, Wilson NO, Crawford S, et al. Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India. Malar J (2008) 7:83. doi:10.1186/1475-2875-7-83
25. Furuta T, Kimura M, Watanabe N. Elevated levels of vascular endothelial growth factor (VEGF) and soluble vascular endothelial growth factor receptor (VEGFR)-2 in human malaria. Am J Trop Med Hyg (2010) 82:136-9. doi:10.4269/ajtmh.2010.09-0203
26. Medana IM, Day NP, Roberts R, Sachanonta N, Turley H, Pongponratn E, et al. Induction of the vascular endothelial growth factor pathway in the brain of adults with fatal falciparum malaria is a non-specific response to severe disease. Histopathology (2010) 57:282-94. doi:10.1111/j.1365-2559.2010.03619.x
27. Conroy AL, Phiri H, Hawkes M, Glover S, Mallewa M, Seydel KB, et al. Endothelium-based biomarkers are associated with cerebral malaria in Malawian children: a retrospective case-control study. PLoS One (2010) 5:e15291. doi:10.1371/journal.pone.0015291
28. Epiphanio S, Campos MG, Pamplona A, Carapau D, Pena AC, Ataide R, et al. VEGF promotes malaria-associated acute lung injury in mice. PLoS Pathog (2010) 6:e1000916. doi:10.1371/journal.ppat.1000916
29. Hein-Kristensen L, Wiese L, Kurtzhals JA, Staalsoe T. In-depth validation of acridine orange staining for flow cytometric parasite and reticulocyte enumeration in an experimental model using Plasmodium berghei. Exp Parasitol (2009) 123:152-7. doi:10.1016/j.exppara.2009.06.010
30. DellaValle B, Staalsoe T, Kurtzhals JA, Hempel C. Investigation of hydrogen sulfide gas as a treatment against P. falciparum, murine cerebral malaria, and the importance of thiolation state in the development of cerebral malaria. PLoS ONE (2013) 8:e59271. doi:10.1371/journal.pone.0059271
31. Curfs JH, Schetters TP, Hermsen CC, Jerusalem CR, van Zon AA, Eling WM. Immunological aspects of cerebral lesions in murine malaria. Clin Exp Immunol (1989) 75:136-40.
32. Development Core R. Team R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing (2008).
33. Core A, Hempel C, Kurtzhals JA, Penkowa M. Plasmodium berghei ANKA: erythropoietin activates neural stem cells in an experimental cerebral malaria model. Exp Parasitol (2011) 127:500-5. doi:10.1016/j.exppara.2010.09.010
34. Newcomb JK, Pike BR, Zhao X, Hayes RL. Concurrent assessment of calpain and caspase-3 activity by means of western blots of protease-specific spectrin breakdown products. Methods Mol Biol (2000) 144:219-23. doi:10.1385/1-59259-050-0:219
35. London NR, Whitehead KJ, Li DY. Endogenous endothelial cell signaling systems maintain vascular stability. Angiogenesis (2009) 12:149-58. doi:10.1007/s10456-009-9130-z
36. Lovegrove FE, Tangpukdee N, Opoka RO, Lafferty EI, Rajwans N, Hawkes M, et al. Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. PLoS One (2009) 4:e4912. doi:10.1371/journal.pone.0004912
37. Wei X, Li Y, Sun X, Zhu X, Feng Y, Liu J, et al. Erythropoietin protects against murine cerebral malaria through actions on host cellular immunity. Infect Immun (2013) 82(1):165-73. doi:10.1128/IAI.00929-13
38. Hempel C, Hyttel P, Staalso T, Nyengaard JR, Kurtzhals JA. Erythropoietin treatment alleviates ultrastructural myelin changes induced by murine cerebral malaria. Malar J (2012) 11:216. doi:10.1186/1475-2875-11-216
39. Hunt NH, Grau GE, Engwerda C, Barnum SR, van der Heyde H, Hansen DS, et al. Murine cerebral malaria: the whole story. Trends Parasitol (2010) 26(6):272-4. doi:10.1016/j.pt.2010.03.006
40. White NJ, Turner GD, Medana IM, Dondorp AM, Day NP. The murine cerebral malaria phenomenon. Trends Parasitol (2009). doi:10.1016/j.pt.2009.10.007
41. Kaya D, Gursoy-Ozdemir Y, Yemisci M, Tuncer N, Aktan S, Dalkara T. VEGF protects brain against focal ischemia without increasing blood - brain permeability when administered intracerebroventricularly. J Cereb Blood Flow Metab (2005) 25:1111-8. doi:10.1038/sj.jcbfm.9600109
42. Argaw AT, Asp L, Zhang J, Navrazhina K, Pham T, Mariani JN, et al. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J Clin Invest (2012) 122(7):2454-68. doi:10.1172/JCI60842
43. Hoang MV, Nagy JA, Fox JE, Senger DR. Moderation of calpain activity promotes neovascular integration and lumen formation during VEGF-induced pathological angiogenesis. PLoS ONE (2010) 5:e13612. doi:10.1371/journal.pone.0013612
44. Su Y, Cui Z, Li Z, Block ER. Calpain-2 regulation of VEGF-mediated angiogenesis. FASEB J (2006) 20:1443-51. doi:10.1096/fj.05-5354com
45. Medana IM, Day NP, Hien TT, Mai NT, Bethell D, Phu NH, et al. Cerebral calpain in fatal falciparum malaria. Neuropathol Appl Neurobiol (2007) 33:179-92. doi:10.1111/j.1365-2990.2006.00777.x
46. Shukla M, Rajgopal Y, Babu PP. Activation of calpains, calpastatin and spectrin cleavage in the brain during the pathology of fatal murine cerebral malaria. Neurochem Int (2006) 48:108-13. doi:10.1016/j.neuint.2005.09.001
47. Das A, Guyton MK, Butler JT, Ray SK, Banik NL. Activation of calpain and caspase pathways in demyelination and neurodegeneration in animal model of multiple sclerosis. CNS Neurol Disord Drug Targets (2008) 7:313-20. doi:10.2174/187152708784936699
48. Hoang MV, Smith LE, Senger DR. Calpain inhibitors reduce retinal hypoxia in ischemic retinopathy by improving neovascular architecture and functional perfusion. Biochim Biophys Acta (2010) 1812(4):549-57. doi:10.1016/j.bbadis.2010.08.008
49. Chavez JC, Baranova O, Lin J, Pichiule P. The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes. J Neurosci (2006) 26:9471-81. doi:10.1523/JNEUROSCI.2838-06.2006
50. Yeo EJ, Cho YS, Kim MS, Park JW. Contribution of HIF-1alpha or HIF-2alpha to erythropoietin expression: in vivo evidence based on chromatin immunoprecipitation. Ann Hematol (2008) 87:11-7. doi:10.1007/s00277-007-0359-6
51. Yeh SH, Ou LC, Gean PW, Hung JJ, Chang WC. Selective inhibition of early-but not late-expressed HIF-1alpha is neuroprotective in rats after focal ischemic brain damage. Brain Pathol (2010) 21(3):249-62. doi:10.1111/j.1750-3639.2010.00443.x
52. Armah HB, Wilson NO, Sarfo BY, Powell MD, Bond VC, Anderson W, et al. Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children. Malar J (2007) 6:147. doi:10.1186/1475-2875-6-147
53. Kanno S, Oda N, Abe M, Terai Y, Ito M, Shitara K, et al. Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells. Oncogene (2000) 19:2138-46. doi:10.1038/sj.onc.1203533
54. Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci (2001) 114:853-65.
55. Schoch HJ, Fischer S, Marti HH. Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain (2002) 125:2549-57. doi:10.1093/brain/awf257
56. Croll SD, Ransohoff RM, Cai N, Zhang Q, Martin FJ, Wei T, et al. VEGF-mediated inflammation precedes angiogenesis in adult brain. Exp Neurol (2004) 187:388-402. doi:10.1016/j.expneurol.2004.02.010
57. Grau GE, Tacchini-Cottier F, Vesin C, Milon G, Lou JN, Piguet PF, et al. TNF-induced microvascular pathology: active role for platelets and importance of the LFA-1/ICAM-1 interaction. Eur Cytokine Netw (1993) 4:415-9.
58. Grau GE, Mackenzie CD, Carr RA, Redard M, Pizzolato G, Allasia C, et al. Platelet accumulation in brain microvessels in fatal pediatric cerebral malaria. J Infect Dis (2003) 187:461-6. doi:10.1086/367960
59. Ma N, Hunt NH, Madigan MC, Chan-Ling T. Correlation between enhanced vascular permeability, up-regulation of cellular adhesion molecules and monocyte adhesion to the endothelium in the retina during the development of fatal murine cerebral malaria. Am J Pathol (1996) 149:1745-62.
60. Conroy AL, Lafferty EI, Lovegrove FE, Krudsood S, Tangpukdee N, Liles WC, et al. Whole blood angiopoietin-1 and -2 levels discriminate cerebral and severe (non-cerebral) malaria from uncomplicated malaria. Malar J (2009) 8:295. doi:10.1186/1475-2875-8-295
61. Jain V, Lucchi NW, Wilson NO, Blackstock AJ, Nagpal AC, Joel PK, et al. Plasma levels of angiopoietin-1 and -2 predict cerebral malaria outcome in Central India. Malar J (2011) 10:383. doi:10.1186/1475-2875-10-383
62. Desruisseaux MS, Machado FS, Weiss LM, Tanowitz HB, Golightly LM. Cerebral malaria: a vasculopathy. Am J Pathol (2010) 176:1075-8. doi:10.2353/ajpath.2010.091090
63. Chen ZY, Asavaritikrai P, Prchal JT, Noguchi CT. Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. J Biol Chem (2007) 282:25875-83. doi:10.1074/jbc.M701988200
64. Hempel C, Combes V, Hunt NH, Kurtzhals JA, Grau GE. CNS hypoxia is more pronounced in murine cerebral than noncerebral malaria and is reversed by erythropoietin. Am J Pathol (2011) 179:1939-50. doi:10.1016/j.ajpath.2011.06.027