Vaso-occlusion in Schimke-immuno-osseous Dysplasia: Is the NO Pathway Involved?

Abstract

Schimke-immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder with the main clinical findings of spondyloepiphyseal dysplasia, nephrotic syndrome, and defective cellular immunity. Vaso-occlusive processes, especially generalized atherosclerosis, are a life-limiting complication in patients with severe SIOD. The nitric oxide synthase (NOS) oxidizes L-arginine to nitric oxide (NO). NO is a potent vasodilator with inhibitory effects on platelet aggregation and the development of atherosclerosis. We hypothesized that reduced NO production due to antagonism of NOS by asymmetric dimethylarginine (ADMA) would be a possible pathophysiological mechanism for vaso-occlusion in SIOD. We tested this hypothesis in 10 patients with SIOD and 10 age-matched healthy controls. Plasma and urine levels of nitrite and nitrate, the indicators of NO synthesis, and of ADMA, an endogenous NOS inhibitor, in children suffering from SIOD were not significantly different from those in the age-matched healthy controls. Our results suggest that the L-arginine/NO pathway is not altered in SIOD. Antagonism of NOS by ADMA does not seem to be the cause of premature general atherosclerosis in SIOD. The underlying pathology of vaso-occlusion in SIOD still remains unclear.

Atherosclerosis - vascular dysfunction - vaso-occlusive disease - asymmetric dimethylarginine - nitrite - nitrate - mass spectrometry

References

• 1 Boerkoel CF, Takashima H, John J, Yan J, Stankiewicz P, Rosenbarker L, Andre JL, Bogdanovic R, Burguet A, Cockfield S, Cordeiro I, Frund S, Illies F, Joseph M, Kaitila I, Lama G, Loirat C, McLeod DR, Milford DV, Petty EM, Rodrigo F, Saraiva JM, Schmidt B, Smith GC, Spranger J, Stein A, Thiele H, Tizard J, Weksberg R, Lupski JR, Stockton DW. Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia.  Nat Genet. 2002;  30 215-220
• 2 Boerkoel CF, O’Neill S, Andre JL, Benke PJ, Bogdanovic R, Bulla M, Burguet A, Cockfield S, Cordeiro I, Ehrich JH, Frund S, Geary DF, Ieshima A, Illies F, Joseph MW, Kaitila I, Lama G, Leheup B, Ludman MD, McLeod DR, Medeira A, Milford DV, Ormala T, Rener-Primec Z, Santava A, Santos, HG, Schmidt B, Smith GC, Spranger J, Zupancic N, Weksberg R. Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature.  Eur J Pediatr. 2000;  159 1-7
• 3 Rees D, Palmer R, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure.  Proc Natl Acad Sci U S A. 1989;  86 3375-3378
• 4 Haynes WG, Noon JP, Walker BR, Webb DJ. Inhibition of nitric oxide synthesis increases blood pressure in healthy humans.  J Hypertens. 1993;  11 1375-1380
• 5 Fozard JR, Part ML. Haemodynamic responses to NG-monomethyl-L-arginine in spontaneously hypertensive and normotensive Wistar-Kyoto rats.  Br J Pharmacol. 1991;  102 823-826
• 6 Leiper JM, Vallance P. The synthesis and metabolism of asymmetric dimethylarginine (ADMA).  Eur J Clin Pharmacol. 2006;  62 ((Suppl 13)) 33-38
• 7 Tsikas D, Boger RH, Sandmann J, Bode-Boger SM, Frolich JC. Endogenous nitric oxide synthase inhibitors are responsible for the L-arginine paradox.  FEBS Lett. 2000;  478 1-3
• 8 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
• 9 Kielstein JT, Tsikas D, Fliser D. Effects of asymmetric dimethylarginine (ADMA) infusion in humans.  Eur J Clin Pharmacol. 2006;  62 ((Suppl 13)) 39-44
• 10 Boger RH, Bode-Boger SM, Brandes RP, Phivthong-ngam L, Bohme M, Nafe R, Mugge A, Frolich JC. Dietary L-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: comparison with lovastatin.  Circulation. 1997;  96 1282-1290
• 11 Lücke T, Marwedel KM, Kanzelmeyer NK, Hori A, Offner G, Kreipe HH, Ehrich JH, Das AM. Generalized atherosclerosis sparing the transplanted kidney in Schimke disease.  Pediatr Nephrol. 2004;  19 672-675
• 12 Spranger J, Hinkel GK, Stoss H, Thoenes W, Wargowski D, Zepp F. Schimke immuno-osseous dysplasia: a newly recognized multisystem disease.  J Pediatr. 1991;  119 64-72
• 13 Tsikas D, Gutzki FM, Stichtenoth DO. Circulating and excretory nitrite and nitrate as indicators of nitric oxide synthesis in humans: methods of analysis.  Eur J Clin Pharmacol. 2006;  62 ((Suppl 13)) 51-59
• 14 Tsikas D, Schubert B, Gutzki FM, Sandmann J, Frolich JC. Quantitative determination of circulating and urinary asymmetric dimethylarginine (ADMA) in humans by gas chromatography-tandem mass spectrometry as methyl ester tri(N-pentafluoropropionyl) derivative.  J Chromatogr B Analyt Technol Biomed Life Sci. 2003;  798 87-99
• 15 Tsikas D. Simultaneous derivatization and quantification of the nitric oxide metabolites nitrite and nitrate in biological fluids by gas chromatography/mass spectrometry.  Anal Chem. 2000;  72 4064-4072
• 16 Tsikas D, Wolf A, Frolich JC. Simplified HPLC method for urinary and circulating creatinine.  Clin Chem. 2004;  50 201-203
• 17 Ehrich JH, Burchert W, Schirg E, Krull F, Offner G, Hoyer PF, Brodehl J. Steroid resistant nephrotic syndrome associated with spondyloepiphyseal dysplasia, transient ischemic attacks and lymphopenia.  Clin Nephrol. 1995;  43 89-95
• 18 Schmidt B, Christen HJ, Herkenrath P, Benz-Bohm G, Muller-Berghaus J, Querfeld U. Cerebral complications in Schimke immuno-osseous dysplasia.  Eur J Pediatr. 1997;  156 789-791
• 19 Boerkoel CF, Nowaczyk MJ, Blaser SI, Meschino WS, Weksberg R. Schimke immuno-osseous dysplasia complicated by moyamoya phenomenon.  Am J Med Genet. 1998;  78 118-122
• 20 Lücke T, Kemper M, Neumaier-Probst E, Bentele K, Spranger J, Kohlschutter A. Das Moya-Moya-Phänomen bei der Immuno-Ossären Dysplasie Schimke. In: Monatsschr Kinderheilkd 1999: 904
• 21 Ehrich JH, Offner G, Schirg E, Hoyer PF, Helmchen U, Brodehl J. Association of spondylo-epiphyseal dysplasia with nephrotic syndrome.  Pediatr Nephrol. 1990;  4 117-121
• 22 Lou S, Lamfers P, McGuire N, Boerkoel CF. Longevity in Schimke immuno-osseous dysplasia.  J Med Genet. 2002;  39 922-925
• 23 Clark JF, Kemp GJ, Radda GK. The creatine kinase equilibrium, free [ADP] and myosin ATPase in vascular smooth muscle cross-bridges.  J Theor Biol. 1995;  173 207-211
• 24 Kim P, Jones JD, Sundt Jr TM. High-energy phosphate levels in the cerebral artery during chronic vasospasm after subarachnoid hemorrhage.  J Neurosurg. 1992;  76 991-996
• 25 Lücke T, Ehrich JH, Das AM. Mitochondrial function in Schimke-immuno-osseous dysplasia.  Metab Brain Dis. 2005;  20 237-242
• 26 Moncada S, Higgs A. The L-arginine-nitric oxide pathway.  N Engl J Med. 1993;  329 2002-2012
• 27 Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease.  Annu Rev Med. 1997;  48 489-509
• 28 Cayatte AJ, Palacino JJ, Horten K, Cohen RA. Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits.  Arterioscler Thromb. 1994;  14 753-759

Correspondence