Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis

English version České info

During a malaria infection, the vascular endothelium becomes more adhesive, permeable, and prone to trigger blood clotting. These changes help the parasite adhere to blood vessels, but endanger the host by obstructing blood flow through small vessels. Endothelial nitric oxide (NO) would normally counteract these pathological changes, but NO signalling is diminished malaria. NO synthesis is inhibited by asymmetric dimethylarginine (ADMA), a methylated derivative of arginine that is released during normal protein turnover. We found the ratio of ADMA to arginine to be elevated in Gambian children with severe malaria, a metabolic disturbance known to inhibit NO synthesis. ADMA was associated with markers of endothelial activation and impaired tissue perfusion. In parallel experiments using mice, the enzyme responsible for metabolizing ADMA, dimethylarginine dimethylaminohydrolase (DDAH), was inactivated after infection with a rodent malaria. Based on these studies, we propose that decreased metabolism of ADMA by DDAH might contribute to the elevated ADMA/arginine ratio observed during an acute episode of malaria. Strategies to preserve or increase DDAH activity might improve NO synthesis and help to prevent the vascular manifestations of severe malaria.

Vyšlo v časopise: Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis. PLoS Pathog 11(9): e32767. doi:10.1371/journal.ppat.1005119
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005119

Souhrn

Zdroje

1. World Health Organization. World malaria report 2014 [Internet]. 2014. Available: http://apps.who.int/iris/bitstream/10665/144852/2/9789241564830_eng.pdf?ua=1

2. Murray CJ, Rosenfeld LC, Lim SS, Andrews KG, Foreman KJ, Haring D, et al. Global malaria mortality between 1980 and 2010: a systematic analysis. The Lancet. 2012;379: 413–431. doi: 10.1016/S0140-6736(12)60034-8

3. Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010;376: 1647–57. doi: 10.1016/S0140-6736(10)61924-1 21062666

4. Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, McNeil YR, et al. Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med. 2007;204: 2693–704. 17954570

5. Anstey NM, Weinberg JB, Hassanali MY, Mwaikambo ED, Manyenga D, Misukonis MA, et al. Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. J Exp Med. 1996;184: 557–67. 8760809

6. Cabrales P, Zanini GM, Meays D, Frangos JA, Carvalho LJ. Nitric oxide protection against murine cerebral malaria is associated with improved cerebral microcirculatory physiology. J Infect Dis. 2011;203: 1454–63. doi: 10.1093/infdis/jir058 21415018

7. Gramaglia I, Sobolewski P, Meays D, Contreras R, Nolan JP, Frangos JA, et al. Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat Med. 2006;12: 1417–1422. doi: 10.1038/nm1499 17099710

8. Serghides L, Kim H, Lu Z, Kain DC, Miller C, Francis RC, et al. Inhaled nitric oxide reduces endothelial activation and parasite accumulation in the brain, and enhances survival in experimental cerebral malaria. PLoS One. 2011;6: e27714. doi: 10.1371/journal.pone.0027714 22110737

9. Serirom S, Raharjo WH, Chotivanich K, Loareesuwan S, Kubes P, Ho M. Anti-adhesive effect of nitric oxide on Plasmodium falciparum cytoadherence under flow. Am J Pathol. 2003;162: 1651–60. 12707049

10. Dondorp AM, Ince C, Charunwatthana P, Hanson J, Kuijen A van, Faiz MA, et al. Direct In Vivo Assessment of Microcirculatory Dysfunction in Severe Falciparum Malaria. J Infect Dis. 2008;197: 79–84. doi: 10.1086/523762 18171289

11. Yeo TW, Lampah DA, Kenangalem E, Tjitra E, Price RN, Anstey NM. Impaired skeletal muscle microvascular function and increased skeletal muscle oxygen consumption in severe falciparum malaria. J Infect Dis. 2013;207: 528–536. doi: 10.1093/infdis/jis692 23162136

12. Dorovini-Zis K, Schmidt K, Huynh H, Fu W, Whitten RO, Milner D, et al. The neuropathology of fatal cerebral malaria in malawian children. Am J Pathol. 2011;178: 2146–2158. doi: 10.1016/j.ajpath.2011.01.016 21514429

13. Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS, Fosiko NG, et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med. 2004;10: 143–5. 14745442

14. Cardounel AJ, Cui H, Samouilov A, Johnson W, Kearns P, Tsai AL, et al. Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function. J Biol Chem. 2007;282: 879–87. doi: 10.1074/jbc.M603606200 17082183

15. Kakimoto Y, Akazawa S. Isolation and Identification of Ng,Ng- and Ng,N’g-Dimethylarginine, Nε-Mono-, Di-, and Trimethyllysine, and Glucosylgalactosyl- and Galactosyl-δ-hydroxylysine from Human Urine. J Biol Chem. 1970;245: 5751–5758. 5472370

16. Lee HW, Kim S, Paik WK. S-Adenosylmethionine:protein-arginine methyltransferase. Purification and mechanism of the enzyme. Biochemistry (Mosc). 1977;16: 78–85. doi: 10.1021/bi00620a013

17. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992;339: 572–575. 1347093

18. Achan V, Broadhead M, Malaki M, Whitley G, Leiper J, MacAllister R, et al. Asymmetric Dimethylarginine Causes Hypertension and Cardiac Dysfunction in Humans and Is Actively Metabolized by Dimethylarginine Dimethylaminohydrolase. Arterioscler Thromb Vasc Biol. 2003;23: 1455–1459. doi: 10.1161/01.ATV.0000081742.92006.59 12805079

19. Kielstein JT, Impraim B, Simmel S, Bode-Böger SM, Tsikas D, Frölich JC, et al. Cardiovascular Effects of Systemic Nitric Oxide Synthase Inhibition With Asymmetrical Dimethylarginine in Humans. Circulation. 2004;109: 172–177. doi: 10.1161/01.CIR.0000105764.22626.B1 14662708

20. Chen M, Li Y, Yang T, Wang Y, Bai Y, Xie X. ADMA induces monocyte adhesion via activation of chemokine receptors in cultured THP-1 cells. Cytokine. 2008;43: 149–159. doi: 10.1016/j.cyto.2008.05.001 18617418

21. Zhang G, Bai Y, Chen M, Shi R, Jiang D, Fu Q, et al. Asymmetric dimethylarginine induces TNF-alpha production via ROS/NF-kappaB dependent pathway in human monocytic cells and the inhibitory effect of reinioside C. Vascul Pharmacol. 2008;48: 115–21. doi: 10.1016/j.vph.2008.01.004 18295546

22. Jiang D, Cao Y, Xin H, Li X, Luo Z, Li Y. Asymmetric dimethylarginine induces tissue factor expression in monocytes via NF-kappaB-dependent pathway: Role in acute coronary syndromes. Atherosclerosis. 2009;205: 554–60. doi: 10.1016/j.atherosclerosis.2008.12.024 19167713

23. Zhang Q, Chen N, Qiu W, Xu X, Wang D, Tsao PS, et al. Asymmetric dimethylarginine impairs fibrinolytic activity in human umbilical vein endothelial cells via p38 MAPK and NF-κB pathways. Thromb Res. 2011;128: 42–46. doi: 10.1016/j.thromres.2011.02.013 21429569

24. Wojciak-Stothard B, Torondel B, Zhao L, Renné T, Leiper JM. Modulation of Rac1 Activity by ADMA/DDAH Regulates Pulmonary Endothelial Barrier Function. Mol Biol Cell. 2009;20: 33–42. doi: 10.1091/mbc.E08-04-0395 18923147

25. Fiedler L, Wojciak-Stothard B. The DDAH/ADMA pathway in the control of endothelial cell migration and angiogenesis. Biochem Soc Trans. 2009;37: 1243–7. doi: 10.1042/BST0371243 19909255

26. Wojciak-Stothard B, Torondel B, Tsang L, Fleming I, Fisslthaler B, Leiper J, et al. The ADMA/DDAH pathway is a critical regulator of endothelial cell motility. J Cell Sci. 2007;120: 929–42. doi: 10.1242/jcs.002212 17327280

27. Achan V, Ho H, Heeschen C, Stuehlinger M, Jang J, Kimoto M, et al. ADMA regulates angiogenesis: genetic and metabolic evidence. Vasc Med Lond Engl. 2005;10: 7–14.

28. Fiedler L, Bachetti T, Leiper J, Zachary I, Chen L, Renné T, et al. The ADMA/DDAH pathway regulates VEGF-mediated angiogenesis. Arterioscler Thromb Vasc Biol. 2009;29: 2117–24. doi: 10.1161/ATVBAHA.109.194035 19778944

29. Dowsett L, Piper S, Slaviero A, Dufton N, Wang Z, Boruc O, et al. Endothelial DDAH1 is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis. Circulation. 2015; doi: 10.1161/CIRCULATIONAHA.114.015064 25910799

30. Zhang P, Xu X, Hu X, Wang H, Fassett J, Huo Y, et al. DDAH1 deficiency attenuates endothelial cell cycle progression and angiogenesis. PloS One. 2013;8: e79444. doi: 10.1371/journal.pone.0079444 24260221

31. Konishi H, Sydow K, Cooke J. Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury. J Am Coll Cardiol. 2007;49: 1099–105. doi: 10.1016/j.jacc.2006.10.068 17349891

32. Wang J, Sim AS, Wang XL, Wilcken DEL. L-arginine regulates asymmetric dimethylarginine metabolism by inhibiting dimethylarginine dimethylaminohydrolase activity in hepatic (HepG2) cells. Cell Mol Life Sci CMLS. 2006;63: 2838–2846. doi: 10.1007/s00018-006-6271-8 17075694

33. Hu T, Chouinard M, Cox AL, Sipes P, Marcelo M, Ficorilli J, et al. Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation. J Biol Chem. 2006;281: 39831–39838. doi: 10.1074/jbc.M606779200 17065154

34. Wang D, Gill PS, Chabrashvili T, Onozato ML, Raggio J, Mendonca M, et al. Isoform-specific regulation by N(G),N(G)-dimethylarginine dimethylaminohydrolase of rat serum asymmetric dimethylarginine and vascular endothelium-derived relaxing factor/NO. Circ Res. 2007;101: 627–635. doi: 10.1161/CIRCRESAHA.107.158915 17673667

35. Jallow M, Teo YY, Small KS, Rockett KA, Deloukas P, Clark TG, et al. Genome-wide and fine-resolution association analysis of malaria in West Africa. Nat Genet. 2009;41: 657–665. doi: 10.1038/ng.388 19465909

36. Siroen MPC, van der Sijp JRM, Teerlink T, van Schaik C, Nijveldt RJ, van Leeuwen PAM. The human liver clears both asymmetric and symmetric dimethylarginine. Hepatology. 2005;41: 559–565. doi: 10.1002/hep.20579 15726655

37. Nijveldt RJ, Teerlink T, Siroen MPC, van Lambalgen AA, Rauwerda JA, van Leeuwen PAM. The liver is an important organ in the metabolism of asymmetrical dimethylarginine (ADMA). Clin Nutr Edinb Scotl. 2003;22: 17–22.

38. Nijveldt RJ, Teerlink T, Siroen MPC, van der Hoven B, Prins HA, Wiezer MJ, et al. Elevation of asymmetric dimethylarginine (ADMA) in patients developing hepatic failure after major hepatectomy. JPEN J Parenter Enteral Nutr. 2004;28: 382–387. 15568284

39. Cardounel AJ, Cui H, Samouilov A, Johnson W, Kearns P, Tsai AL, et al. Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function. J Biol Chem. 2007;282: 879–87. doi: 10.1074/jbc.M603606200 17082183

40. Taylor TE, Borgstein A, Molyneux ME. Acid-base status in paediatric Plasmodium falciparum malaria. Q J Med. 1993;86: 99–109. 8464997

41. Krishna S, Waller DW, ter Kuile F, Kwiatkowski D, Crawley J, Craddock CF, et al. Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance. Trans R Soc Trop Med Hyg. 1994;88: 67–73. 8154008

42. Waller D, Krishna S, Crawley J, Miller K, Nosten F, Chapman D, et al. Clinical features and outcome of severe malaria in Gambian children. Clin Infect Dis. 1995;21: 577–87. 8527547

43. Planche T, Agbenyega T, Bedu-Addo G, Ansong D, Owusu-Ofori A, Micah F, et al. A Prospective Comparison of Malaria with Other Severe Diseases in African Children: Prognosis and Optimization of Management. Clin Infect Dis. 2003;37: 890–897. doi: 10.1086/377536 13130399

44. Blumberg BS, Kuvin SF, Robinson JC, Teitelbaum JM, Contacos PG. Alterations in haptoglobin levels. JAMA. 1963;184: 1021–1023. 13971874

45. Kleinbongard P, Dejam A, Lauer T, Rassaf T, Schindler A, Picker O, et al. Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic Biol Med. 2003;35: 790–796. doi: 10.1016/S0891-5849(03)00406-4 14583343

46. Weinberg JB, Yeo TW, Mukemba JP, Florence SM, Volkheimer AD, Wang H, et al. Dimethylarginines: endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria. J Infect Dis. 2014; jiu156. doi: 10.1093/infdis/jiu156 24620026

47. Molyneux ME, Looareesuwan S, Menzies IS, Grainger SL, Phillips RE, Wattanagoon Y, et al. Reduced Hepatic Blood Flow and Intestinal Malabsorption in Severe Falciparum Malaria. Am J Trop Med Hyg. 1989;40: 470–476. 2729505

48. Jiang J-L, Wang S, Li N-S, Zhang X-H, Deng H-W, Li Y-J. The inhibitory effect of simvastatin on the ADMA-induced inflammatory reaction is mediated by MAPK pathways in endothelial cells. Biochem Cell Biol Biochim Biol Cell. 2007;85: 66–77. doi: 10.1139/o06-146

49. Chan JR, Böger RH, Bode-Böger SM, Tangphao O, Tsao PS, Blaschke TF, et al. Asymmetric Dimethylarginine Increases Mononuclear Cell Adhesiveness in Hypercholesterolemic Humans. Arterioscler Thromb Vasc Biol. 2000;20: 1040–1046. doi: 10.1161/01.ATV.20.4.1040 10764670

50. Böger R, Bode-Böger S, Tsao P, Lin P, Chan J, Cooke J. An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes. J Am Coll Cardiol. 2000;36: 2287–95. 11127475

51. Dondorp AM, Desakorn V, Pongtavornpinyo W, Sahassananda D, Silamut K, Chotivanich K, et al. Estimation of the Total Parasite Biomass in Acute Falciparum Malaria from Plasma PfHRP2. PLoS Med. 2005;2: e204. doi: 10.1371/journal.pmed.0020204 16104831

52. Cunnington AJ, Bretscher MT, Nogaro SI, Riley EM, Walther M. Comparison of parasite sequestration in uncomplicated and severe childhood Plasmodium falciparum malaria. J Infect. 2013;67: 220–230. doi: 10.1016/j.jinf.2013.04.013 23623771

53. Yeo TW, Lampah DA, Tjitra E, Gitawati R, Darcy CJ, Jones C, et al. Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome. PLoS Pathog. 2010;6: e1000868. doi: 10.1371/journal.ppat.1000868 20421938

54. Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol. 2005;4: 827–40. 16297841

55. Weiss SL, Haymond S, Ranaivo HR, Wang D, De Jesus VR, Chace DH, et al. Evaluation of asymmetric dimethylarginine, arginine, and carnitine metabolism in pediatric sepsis. Pediatr Crit Care Med July 2012. 2012;13. doi: 10.1097/PCC.0b013e318238b5cd

56. Brenner T, Fleming TH, Rosenhagen C, Krauser U, Mieth M, Bruckner T, et al. L-Arginine and Asymmetric Dimethylarginine Are Early Predictors for Survival in Septic Patients with Acute Liver Failure. Mediators Inflamm. 2012;2012: e210454. doi: 10.1155/2012/210454

57. O’Dwyer MJ, Dempsey F, Crowley V, Kelleher DP, McManus R, Ryan T. Septic shock is correlated with asymmetrical dimethyl arginine levels, which may be influenced by a polymorphism in the dimethylarginine dimethylaminohydrolase II gene: a prospective observational study. Crit Care Lond Engl. 2006;10: R139. doi: 10.1186/cc5053

58. Davis JS, Darcy CJ, Yeo TW, Jones C, McNeil YR, Stephens DP, et al. Asymmetric Dimethylarginine, Endothelial Nitric Oxide Bioavailability and Mortality in Sepsis. PLoS ONE. 2011;6: e17260. doi: 10.1371/journal.pone.0017260 21364995

59. Davids M, van Hell AJ, Visser M, Nijveldt RJ, van Leeuwen PAM, Teerlink T. Role of the human erythrocyte in generation and storage of asymmetric dimethylarginine. AJP Heart Circ Physiol. 2012;302: H1762–H1770. doi: 10.1152/ajpheart.01205.2011

60. Bogle RG, MacAllister RJ, Whitley GS, Vallance P. Induction of NG-monomethyl-L-arginine uptake: a mechanism for differential inhibition of NO synthases? Am J Physiol-Cell Physiol. 1995;269: C750–C756.

61. Closs EI, Basha FZ, Habermeier A, Forstermann U. Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier hCAT-2B. Nitric Oxide. 1997;1: 65–73. doi: 10.1006/niox.1996.0106 9701046

62. Hatzoglou M, Fernandez J, Yaman I, Closs E. Regulation of cationic amino acid transport: the story of the CAT-1 transporter. Annu Rev Nutr. 2004;24: 377–99. doi: 10.1146/annurev.nutr.23.011702.073120 15459982

63. Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O’Hara B, et al. Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med. 2007;13: 198–203. doi: 10.1038/nm1543 17273169

64. Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang B, et al. Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis Genetic and Physiological Evidence. Circulation. 2003;108: 3042–3047. doi: 10.1161/01.CIR.0000101924.04515.2E 14638548

65. Leiper JM, Santa Maria J, Chubb A, MacAllister RJ, Charles IG, Whitley GS, et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J. 1999;343 Pt 1: 209–214. 10493931

66. Hu X, Xu X, Zhu G, Atzler D, Kimoto M, Chen J, et al. Vascular Endothelial-Specific Dimethylarginine Dimethylaminohydrolase-1–Deficient Mice Reveal That Vascular Endothelium Plays an Important Role in Removing Asymmetric Dimethylarginine. Circulation. 2009;120: 2222–2229. doi: 10.1161/CIRCULATIONAHA.108.819912 19917889

67. Siroen MPC, Warlé MC, Teerlink T, Nijveldt RJ, Kuipers EJ, Metselaar HJ, et al. The transplanted liver graft is capable of clearing asymmetric dimethylarginine. Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc. 2004;10: 1524–1530. doi: 10.1002/lt.20286

68. Mookerjee RP, Dalton RN, Davies NA, Hodges SJ, Turner C, Williams R, et al. Inflammation is an important determinant of levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in acute liver failure. Liver Transpl. 2007;13: 400–405. doi: 10.1002/lt.21053 17318866

69. Griffiths MJ, Ndungu F, Baird KL, Muller DPR, Marsh K, Newton CRJC. Oxidative stress and erythrocyte damage in Kenyan children with severe Plasmodium falciparum malaria. Br J Haematol. 2001;113: 486–491. doi: 10.1046/j.1365-2141.2001.02758.x 11380421

70. Rubach MP, Mukemba J, Florence S, Lopansri BK, Hyland K, Volkheimer AD, et al. Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severity. PLoS Pathog. 2015;11: e1004655. doi: 10.1371/journal.ppat.1004655 25764173

71. Luo Z, Teerlink T, Griendling K, Aslam S, Welch WJ, Wilcox CS. Angiotensin II and NADPH Oxidase Increase ADMA in Vascular Smooth Muscle Cells. Hypertension. 2010;56: 498–504. doi: 10.1161/HYPERTENSIONAHA.110.152959 20696982

72. Dey S, Bindu S, Goyal M, Pal C, Alam A, Iqbal MS, et al. Impact of Intravascular Hemolysis in Malaria on Liver Dysfunction INVOLVEMENT OF HEPATIC FREE HEME OVERLOAD, NF-κB ACTIVATION, AND NEUTROPHIL INFILTRATION. J Biol Chem. 2012;287: 26630–26646. doi: 10.1074/jbc.M112.341255 22696214

73. Seydel KB, Milner DA, Kamiza SB, Molyneux ME, Taylor TE. The Distribution and Intensity of Parasite Sequestration in Comatose Malawian Children. J Infect Dis. 2006;194: 208–215. doi: 10.1086/505078 16779727

74. Billecke SS. Contribution of whole blood to the control of plasma asymmetrical dimethylarginine. AJP Heart Circ Physiol. 2006;291: H1788–H1796. doi: 10.1152/ajpheart.00066.2006

75. Davids M, van Hell AJ, Visser M, Nijveldt RJ, van Leeuwen PAM, Teerlink T. Role of the human erythrocyte in generation and storage of asymmetric dimethylarginine. Am J Physiol Heart Circ Physiol. 2012;302: H1762–1770. doi: 10.1152/ajpheart.01205.2011 22367507

76. Teerlink T, Luo Z, Palm F, Wilcox C. Cellular ADMA: regulation and action. Pharmacol Res Off J Ital Pharmacol Soc. 2009;60: 448–60. doi: 10.1016/j.phrs.2009.08.002

77. Masuda H, Goto M, Tamaoki S, Azuma H. Accelerated intimal hyperplasia and increased endogenous inhibitors for NO synthesis in rabbits with alloxan-induced hyperglycaemia. Br J Pharmacol. 1999;126: 211–218. doi: 10.1038/sj.bjp.0702298 10051138

78. Faraci FM, Brian JE, Heistad DD. Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am J Physiol. 1995;269: H1522–1527. 7503244

79. Smith C, Anthony S, Hubank M, Leiper J, Vallance P. Effects of ADMA upon gene expression: an insight into the pathophysiological significance of raised plasma ADMA. PLoS Med. 2005;2: e264. doi: 10.1371/journal.pmed.0020264 16190779

80. De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96: 60–8. 7542286

81. Walther M, Jeffries D, Finney OC, Njie M, Ebonyi A, Deininger S, et al. Distinct roles for FOXP3 and FOXP3 CD4 T cells in regulating cellular immunity to uncomplicated and severe Plasmodium falciparum malaria. PLoS Pathog. 2009;5: e1000364. doi: 10.1371/journal.ppat.1000364 19343213

82. Guidelines for the Management of Malaria. Banjul, The Gambia: Ministry of Health and Social Welfare; 2005.