Homocysteine atherosclerosis

Homocysteine arises from dietary methionine. High levels of homocysteiae (hyperhomocysteinemia) are a risk factor for occlusive vascular diseases including atherosclerosis and thrombosis (81—84). In a controlled study, semm folate concentrations of <9.2 nmol/L were linked with elevated levels of plasma homocysteiae. Elevated homocysteine levels have beea associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, aot completely uaderstood. lateractioa of homocysteiae with platelets or eadothehal cells has beea proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by administration of vitamin B, vitamin B 2> foHc acid. 

Homocysteine has been identified as an independent risk factor for atherosclerosis (32) and thus metaboHc control over homocysteine levels has major health implications. 

Methyl-tetrahydro folic acid is furthermore, together with vitamin B12 and B6, required to regenerate homocysteine (see Vitamin B12, Fig. 1). Homocysteine results when methionine is used as a substrate for methyl group transfer. During the last few years, homocysteine has been acknowledged as an independent risk factor in atherosclerosis etiology. Folic acid supplementation can help reduce elevated homocysteine plasma levels and is therefore supposed to reduce the risk of atherosclerosis as well [2]. 

Supplements of 400 Ig/d of folate begun before conception result in a significant reduction in the incidence of neural mbe defects as found in spina bifida. Elevated blood homocysteine is an associated risk factor for atherosclerosis, thrombosis, and hypertension. The condition is due to impaired abihty to form methyl-tetrahydrofolate by methylene-tetrahydrofolate reductase, causing functional folate deficiency and resulting in failure to remethylate homocysteine to methionine. People with the causative abnormal variant of methylene-tetrahydrofolate reductase do not develop hyperhomocysteinemia if they have a relatively high intake of folate, but it is not yet known whether this affects the incidence of cardiovascular disease. 

Growing clinical data also points to the importance of IL-8 in atherogenesis. IL-8 has been found in atheromatous lesions from patients with atherosclerotic disease including carotid artery stenosis (103), CAD (118), abdominal aortic aneurysms (AAA) (103,104,114), and peripheral vascular disease (PVD) (104). Furthermore, studies using plaque explant samples have yielded more direct evidence for IL-8 involvement. Media from cultured AAA tissue induced IL-8-dependent human aortic endothelial cell (HAEC) chemotaxis (122). Homocysteine, implicated as a possible biomarker for CAD, is also capable of inducing IL-8 (123-125) by direct stimulation of endothelial cells (123,124) and monocytes (125). When patients with hyperhomocysteinemia were treated with low-dose folic acid, decreases in homocysteine levels correlated with decreases in IL-8 levels (126). Statins significantly decrease serum levels of IL-6, IL-8, and MCP-1, as well as expression of IL-6, IL-8, and MCP-1 mRNA by peripheral blood monocytes and HUVECs (127). Thus, IL-8 may be an underappreciated factor in the pathogenesis of atherosclerosis. 

The response-to-injury hypothesis states that risk factors such as oxidized LDL, mechanical injury to the endothelium, excessive homocysteine, immunologic attack, or infection-induced changes in endothelial and intimal function lead to endothelial dysfunction and a series of cellular interactions that culminate in atherosclerosis. The eventual clinical outcomes may include angina, myocardial infarction, arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Homocysteine blood levels (>15 jtmol/L) promote atherosclerosis, perhaps by stimulating proliferation of arterial wall smooth muscle cells. Supplementing the diet with folic acid can reduce high levels. Lpa is a mod-ihed LDL particle that is both atherogenic and pro-thrombic. 

Reported rate constants for the reaction of 02 with GSH have varied from 102 to > 105 M 1 s. A re-examination of this reaction by spin trapping with DMPO established that earlier studies had been confounded by the direct reduction of the DMPO/ OOH adduct to DMPO/ OH by GSH. Taking account of this reaction, the revised rate constant was reported to be 200 M-1 g-i.25i.2S2 other workers have examined, for example, the effects of GSH and N-acetyl-L-cysteine on lipid peroxidation 253 and the role of GS in the toxicity of the diabetogenic agent alloxan.254 Direct EPR has been used to detect binuclear Cu(II) complexes of homocysteine. The interactions of such complexes with blood-vessel linings may account for the link between elevated homocysteine and atherosclerosis.255... 

Giral P, Bruckert E, Jacob N, Chapman MJ, Foglietti MJ, Turpin G. Homocysteine and lipid lowering agents. A comparison between atorvastatin and fenofibrate in patients with mixed hyperlipidemia. Atherosclerosis 2001 154(2) 421-7. 

Compared with healthy controls, 51 patients with epilepsy taking a variety of antiepileptic drugs (mostly carbamaze-pine) had higher mean plasma concentrations of homocysteine (130). This effect, which could be related to reductions in the concentrations of folate and vitamin B6, was likely to be drug-induced, but a causative role of the underlying disease could not be excluded. Although homocysteine is an experimental convulsant and a risk factor for atherosclerosis, the clinical relevance of these findings is uncertain. 

Rea IM, McMaster D, Woodside JV, Young IS, Archbold GP, Linton T, Lennox S, McNulty H, Harmon DL, Whitehead AS. Community-living nonagenarians in Northern Ireland have lower plasma homocysteine but similar methylenetetrahydrofolate reductase thermolabile genotype prevalence compared to 70-89-year-old subjects. Atherosclerosis 2000 149 207-214. 

Homocysteine is a nonprotein-building amino acid formed as a metabolite in the methionine cycle. It was first associated with disease in 1962 (1,2). Individuals with a mutation in cystathionine-(3-synthase (CBS) develop classical homocystin-uria with extremely elevated plasma tHcy (> 100 xmol/L) (3). Homocystinuria is characterized by early atherosclerosis and thromboembolism as well as mental retardation and osteoporosis and is ameliorated by vitamin supplementation aimed at reducing the blood concentration of homocysteine (4). 

Increases in plasma S-AA levels have previously been reported in patients with coronary disease (57). S-AA and plasma intracellular adhesion molecule-1 were elevated in patients with CAD and hyperhomocysteinemia, but only S-AA decreased after vitamin supplementation (35). Homocysteine activates nuclear factor- in endothelial cells, possibly via oxidative stress (58), and increases monocyte chemoattractant protein-1 expression in vascular smooth muscle cells (59). Additionally, it stimulates interleukin-8 expression in human endothelial cultures (60). These inflammatory factors are known to participate in the development of atherosclerosis. Taken together, these reports suggest an association of elevated tHcy and low-grade inflammation in CAD. 

Brilakis ES, et al. Lack of association between plasma homocysteine and angiographic coronary artery disease in the era of fortification of cereal grain flour with folic acid. Atherosclerosis 2002 165(2) 375 381. 

Lange S, Trampisch HJ, Haberl R, et al. Excess I-year cardiovascular risk in elderly primary care patients with a low ankle-brachial index (ABI) and high homocysteine level. Atherosclerosis 2005 178(2) 351 -357. 

Audelin MC, Genest J Jr. 2001. Homocysteine and cardiovascular disease in diabetes mellitus. Atherosclerosis 159(2) 497—511. 

Fonseca VA, Fink UM, Kern PA. 2003. Insulin sensitivity and plasma homocysteine concentrations in non diabetic obese and normal weight subjects. Atherosclerosis 167 105-109. 

Giltay EJ, Hoogeveen EK, Elbers JM, Gooren U, Asscheman H, Stehouwer CD. 1998. Insulin resistance is associated with elevated plasma total homocysteine levels in healthy, non obese subjects. Atherosclerosis 139 197-198. 

The commonly recognized risk factors for atherosclerosis include increasing age, sex (males > females until menopause, after which the incidence is similar), serum lipid levels (increased total cholesterol and low-density lipoprotein cholesterol, decreased high-density lipoprotein cholesterol, etc.), diabetes melli-tus, hypertension, and obesity. Other less well recognized but very important risk factors include increased plasma homocysteine, fibrinogen, and coagulation factor VII increased blood hematocrit, leukocyte count (increased neutrophils), and C-reactive protein and clinical depression. 

The identification of hyperhomocysteinemia as an independent risk factor in atherosclerosis and coronary heart disease (Section 10.3.4.2) has led to suggestions that intakes of vitamin Be higher than are currently considered adequate to meet requirements may be desirable. Homocysteine is an intermediate in methionine metabolism and may undergo one of two metabolic fates, as shown in Figure 9.5 remethylation to methionine (a reaction that is dependent on vitamin B12 and folic acid) or onward metabolism leading to the synthesis of cysteine (trans-sulfuration). Therefore, intakes of folate, vitamin B12, and/or vitamin Be may affect homocysteine metabolism. 

Yeun JY and Kaysen GA, C-reactive protein, oxidative stress, homocysteine, and troponin as inflammatory and metabolic predictors of atherosclerosis in ESRD. Curr Opin Nephrol Hypertens 9(6) 621-30,2000. 

C. J. Glueck, P. Shaw, J. E. Lang, T. Tracy, L. Sieve-Smith and Y. Wang, Evidence That Homocysteine is an Independent Risk Factor for Atherosclerosis in H)T3erlipidemic Patients, American Journal of Cardiology 75 (1995) 132-136. 

Homocysteine A Link to Atherosclerosis, Proceedings of National Academy of Sciences USA 91 (1994)6369-6373. 

A consequence of these studies is that the Food and Drug Administration (fTDA) has recomtnended that commercially available flour and cereal products be fortified w ith folic acid 1-4 tug folic acid/kg flour) for preventing NTDs (Tucker cf ai, 1996). The consumer interested in the folate level in any particular food can view the label on the package. Folic acid supplements have the effect of reducing the level of homocysteine in the blood. This homocysteine effect appears directly relevant to the prevention of atherosclerosis, but may also be relevant to neural tube defects. The reader interested in continuing developments regarding neural tube defects and folate should take note of the relationship between folate and homocysteine, presented in the Vitamin 8 section. 

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