Angiogenic Diseases
There is little dietary intake or excretion of Homocysteine (Hcy); virtually all of the Hcy in the body is formed and removed by endogenous metabolism.381 Homocysteine metabolism has been identified as a risk factor in congenital heart defects. Meta-analysis research has demonstrated that maternal Hcy was significantly associated with an increased risk of having a child with a Congenital Heart Defect (CHD).382,383,
Homocysteine metabolism is associated with neurological diseases including neural tube defect.384,385,386 Neural tube defects (NTD) are among the most common birth defects worldwide.
Homocysteine metabolism has been documented as a risk factor of Down Syndrome (DS). An elevated risk for DS has been observed with irregular homocysteine metabolism.387 Research has demonstrated a positive relationship between homocysteine levels and increased hostile behaviour in schizophrenia.388
381 Yap S. Classical homocystinuria: Vascular risk and its prevention. J Inherit Metab Dis. 2003;26:259-265
382 Verkleij-Hagoort A, Bliek j, Sayed-Tabatabaei F, Ursem n, Steegers E, Steegers- Theunissen R. Hyperhomocysteine-mia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: a meta-analysis. Am J Med Genet A 2007; 143A:- 952-960.
383 Botto LD, Correa , Erickson JD. Racial and temporal variations in the prevalence of heart defects. Pediatrics 200; 107:E32.
384 Steegers-Theunissen RP, Boers GH, Trijbels fj. Finkelstein jd, Blom hj, Thomas CM, et al. Maternal hyperhomocysyeinemia: a risk factor for neural-tube defects?
Metabolism 1994; 43: 1475-1480
385 Ratan SK, Rattan KN, Pandey RM, Singhal S, Kharab S, Bala M, Singh V, Jhanwar A, Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their matched controls. Pediatr Surg Int. 2008 Jul;24(7):803-8. Epub 2008 May 8.
386 Brustolin S, Guigliana R, Felix T.T, Genetics of homocysteine metabolism and
associated disorders. Brazialian Journal of Medical and Biological Research (2010) 43: 1-7
387 Bosco P, Gueant-Rodriguez RM, Anello G, Barone C, Namour F, Caraci F, et al. Methionine synthase (MTR) 2756 (A --> G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. Am J Med Genet A. 2003 Sep 1;121A(3):219-24.
388 Panagiotakos DB, Pitsavos C, Chrysohoou C, Tsetsekou E, Papageorgiou C, Christodoulou G, Stefanadis C. Increased plasma homocysteine concentrations in healthy people with hostile behavior: the ATTICA study. Med Sci Monit. 2004 Aug;10(8):CR457-62. Epub 2004 Jul 23.
Young male schizophrenic patients were found to have elevated homocysteine levels as were young male patient with bipolar disorder.389 Elevated homocysteine levels have also been found to be associated with depression. Recent research demonstrated that major depression in patients with moderate Alzheimer‘s disease (AD) was associated with higher plasma homocysteine levels.390 Three recent case-control studies, from the United Kingdom391,392 and Sweden393, have reported a correlation between AD and high homocysteine levels. Homocysteine may also be an important factor in Parkinson‘s disease. Kuhn et al.394,395 found elevated of plasma homocysteine in Parkinsonian patients. Furthermore, it has been found that a high plasma concentration of homocysteine may contribute to epilepsy.396 This is of critical importance as Ireland has one of the highest incidences of epilepsy in the world.397,398
It has been found that homocysteine (Hcy) inhibits DNA methylation and endothelial cell (EC) growth, resulting in a disturbance of the angiogenic balance of the body and reduced formation of new blood vessels essential for fetal development, tissue regeneration and wound healing. Angiogenesis (the formation of new blood vessels) also plays a supporting role in pathological conditions such as solid tumour growth, rheumatoid arthritis, and diabetic retinopathy.399,400 Inhibition of angiogenesis reduces blood vessel
389 Levine J, Sela BA, Osher Y, Belmaker RH. High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Prog
Neuropsychopharmacol Biol Psychiatry. 2005 Sep;29(7):1181-91.
390 Sheng C C, Chuan M C, Chun Y Y, Han Y Y, Lian L C, Fang Y C, Kuan L C, Cheng L Y, Plasma Homocysteine Levels and Major Depressive Disorders in Alzheimer Disease, American Journal of Geriatric Psychiatry: November 2010 - Volume 18 - Issue 11 - pp 1045-1048.
391 Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998;55:1449-1455.
392 McCaddon A, Davies G, Hudson P, Tandy S, Cattell H. Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry. 1998;13:235-239. 393 Lehmann M, Gottfries CG, Regland B. Identification of cognitive impairment in the elderly: homocysteine is an early marker. Dement Geriatr Cogn Disord. 1999; 10:12-20.
394 Kuhn W, Roebroek R, Blom H, et al. Elevated plasma levels of homocysteine in Parkinson‘s disease. Eur Neurol. 1998;40:225-227.
395 Muller T, Werne B, Fowler B, Kuhn W. Nigral endothelial dysfunction, homocysteine, and Parkinson‘s disease. Lancet. 1999;354:126-127.
396 Schwarz S, Zhou G-Z. N-methyl-D-aspartate receptors and CNS symptoms of homocystinuria. Lancet. 1991;337:1226-1227.
397 Linehan, C,. Walsh, P A,. The prevlance of Epilepsy in Ireland, Brainwave The Irish Epilepsy Association. 2009
398 L Forsgren, E Beghi, A Oun, M Sillanpää. The epidemiology of epilepsy in Europe - a systematic review. European Journal of Neurology Volume 12. Issue: 4, Pages 245-253 399 Jamaluddin, M,S,. Chen,I,. Yang,F,. Jiang, X., Jan, M., Liu, X., Schafer, A,I,. Durante, W., Yang, X,. Wang, H. Homocysteine inhibits endothelial cell growth via
DNAhypomethylation of thecyclin A gene, Blood Journal 2007 110: 3648-3655
400 Joseph F. Murphy and Desmond. J. Fitzgerald, Vascular endothelial cell growth factor (VEGF) induces cyclooxygenase (COX)-dependent proliferation of endothelial
growth and collateral arteries formation reducing blood flow and oxygen delivery within the body that can lead to cardiac ischaemia, as well as peripheral artery disease. The absence of blood vessels in a repairing or otherwise metabolically active tissue may inhibit repair or other essential functions. The damage is the result of the build-up of metabolic waste products, inability to maintain cell membranes, mitochondrial damage, and eventual leakage of autolyzing proteolytic enzymes into the cell and surrounding tissues. Angiogenesis is also important in leukocyte extravasation and thus the pathogenesis of inflammatory rheumatoid arthritis.401
DNA methylation is an important epigenetic mechanism that selectively regulates gene expression, and is associated with cancer development and cardiovascular disease.402,403 Regulation of gene expression whereby neurons and neuronal networks adapt their short- and long-term responses to environmental stimuli represents a major component of neurological disease.404 A limited number of genes, estimated to be in the range of 15 to 300, show activity-dependent upregulation in the nervous system, whereas the number of genes down-regulated is much lower, suggesting that gene induction is the favoured process for long-term neuronal adaptations.405 Activation of gene expression was shown to be involved in a large variety of processes in both the developing and mature nervous system, including proliferation of neuronal precursors, outgrowth of neuronal processes, learning and memory in invertebrates and vertebrates, induction of neurotrophic and neuroprotectant cellular programs, and regulation of circadian rhythms.406,407,408,409,410
cells (EC) via the VEGF-2 receptor, The FASEB Journal express article 10.1096/fj.00- 0757fje. Published online May 29, 2001.
401 Z Szekanecz; G Szegedi; A E Koch, Angiogenesis in rheumatoid arthritis: pathogenic and clinical significance. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 1998;46(2):27-41.
402 Hiltunen MO, Yla-Herttuala S. DNA methylation, smooth muscle cells, and atherogenesis. Arterioscler Thromb Vasc Biol. 2003;23:1750-1753.
403 Dong C, Yoon W, Goldschmidt-Clermont PJ. DNA methylation and atherosclerosis. J Nutr. 2002; 132:2406S-2409S.
404 Tardito D, Perez J, Tiraboschi E, Musazzi L, Racagni G, Popoli, M. Signalling Pathways Regulating Gene Expression, Neuroplasticity, and Neurotrophic Mechanisms in the Action of Antidepressants: A Critical Overview,
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405 West AE, Griffith EC, and Greenberg ME (2002) Regulation of transcription factors by neuronal activity. Nature Rev Neurosci 3:921–931.
406 Kandel ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science (Wash DC) 294:1030–1038.
407 Mabuchi T, Kitagawa K, Kuwabara K, Takasawa K, Ohtsuki T, Xia Z, Storm D, Yanagihara T, Hori M, and Matsumoto M (2001) Phosphorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo. J Neurosci 21:9204– 9213 408 Reppert SM and Weaver DR (2001) Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol 63:647–676.
Fluoride exposure may therefore be seen to play a leading role in the development of both neurological and angiogenic diseases.