Endothelial cells homocysteine

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. 

Poddar R, Sivasubramanian N, DiBello PM, Robinson K, Jacobsen DW. Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells implications for vascular disease. Circulation 2001 103(22) 2717-2723. 

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.

Prescribing perspective is to recognize that the previously acceptable counts, on treatment, between (500-650) X (f are hazardous since microvas-cular occlusion, including stroke, remain risks. The concurrent role of aspirin continues to be defined. Thus, while this has a sound theoretical benefit and is recommended to decrease platelet-endothelial cell interaction, occasional gastrointestinal tract bleeding may be found. Furthermore, associated hypercoagulability may be found and determinations of proteins C and S, mutations of factor V and II or elevated homocysteine, as well as the presence of anti-cardiolipin syndrome or lupus anticoagulant should not be overlooked. 

Hajjar, K.A., 1993, Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J. Clin. Invest 91, 2873-2879. 

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. 

I Wall RT et al. Homocysteine-induced endothelial cell injury in vitro a model for the study of vascular injury. Thromb Res 1980 18(1-2) I 13-121. 

Geisel J, et al. Stimulatory effect of homocysteine on interleukin-8 expression in human endothelial cells. Clin Chem Lab Med 2003 41 (8) 1045-1048. 

The fraction of intracellular homocysteine that does not undergo transsulfuration or remethylation is secreted into the extracellular space and ultimately finds its way into the blood. One major source of blood homocysteine is the liver, but some homocysteine is secreted into the blood by endothelial cells, circulating blood cells, and other tissues. Only about 2% of homocysteine in blood remains in its reduced, thiol form. The remainder circulates as a variety of different oxidation adducts, which include the disulfide, homocystine, as well as homocysteine-cysteine mixed disulfide and several protein-bound disulfides.About 70% of total homocysteine in blood is bound to the protein albumin through a disulfide linkage.When blood homocysteine is measured in the clinical laboratory, a reducing agent is added to the sample... 

Normal endothelial cells modulate the effects of homocysteine by facilitating the S-nitrosilation of homocysteine by nitric oxide. The formed S-nitrosothiol adduct is a potent vasorelaxing substance [2,108]. So, when high levels of homocysteine occur, they may overcome or impair the endothelial capacity for NO synthesis. Endothelial cell damage may result from increased production of reactive oxygen species or from impaired production of nitric oxide [3,102]. In endothelial cells, total homocysteine reduces the levels of tetra-hydrobiopterin (BH4), relative to dihydrobiopterin (BH ), thereby creating a dysfunctional eNOS causing a reduced amount of nitric oxide [1,101],... 

H. Li, S. Brodsky, S. Kumari, V. Valiunas, P. Brink, J. Kaide, A. Nasjletti, M.S. Goligorsky, Paradoxical overexpression and translocation of connexin 43 in homocysteine-treated endothelial cells, Am J Physiol Heart Circ Physiol 282, H2124-H2133 (2002). 

In plasma, homocysteine is present as both free (< 1 %) and oxidized forms (>99%). The oxidized forms include protein (primarily albumin)-bound homocysteine mixed disulfide (80-90%), homocysteine-cysteine mixed disulfide (5-10%), and homocystine (5-10%). Several studies have shown the relationship between homocysteine and altered endothelial cell function leading to thrombosis. Thus, hyperhomocysteinemia appears to be an independent risk factor for occlusive vascular disease. Five to ten percent of the general population have mild hyperhomocysteinemia. 

Perhaps the most satisfying hypothesis for the formation of atherosclerotic lesions is that of response to injury in which lesions are precipitated by some form of injury to endothelial cells. The injury may be caused by elevated plasma levels of LDL and modified LDL (oxidized LDL), free radicals (e.g., caused by cigarette smoking), diabetes mellitus, hypertension-induced shear stress, and other factors that lead to focal desquamation of endothelial cells such as elevated plasma homocysteine levels, genetic... 

EC-SOD expression is substantially reduced in patients with coronary artery disease and appears to contribute to endothelial dysfunction in patients with this disease [188]. Overexpression of EC-SOD in vascular endothelial cells can protect against the oxidation of LDL, a major factor contributing to the development of atherosclerosis [ 189]. However, a positive correlation was found between the plasma level of EC-SOD and plasma homocysteine level (a risk... 

Kokame K, Kato H, Miyata T. Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis, GRP78/BiP and novel genes. J Biol Chem 1996 271 29659-29665. 

In the presence of physiological concentrations of homocysteine, methionine, and folic acid, human umbilical vein endothelial cells efficiently convert homocysteine to thiolactone (Jakubowski et al. 2000). The extent of this conversion is directly proportional to homocysteine concentration and inversely proportional to methionine concentration, suggesting involvement of methionyl-tRNA synthetase. FoHc add inhibited the synthesis of thiolactone by lowering homocysteine and increasing methionine concentrations in endotheUal cells. The extent of post-translational protein homocystei-nylation increased with increasing homocysteine levels but decreased with increasing folic acid and HDL levels in endotheUal cell cultures. 

The associations between issues B, C and vitamin B12 are discussed here. Concerning issue A, oxidative stress by free radicals formed during the reducing process of homocysteine is reported to injure endothelial cells directly (Mansoor et al. 1995). 

Vitamin Bg in its various forms has antioxidant properties that compare favorably with those of the well-established antioxidant vitamins such as vitamin C and the tocopherols. Pyridoxine and pyridoxamine inhibit superoxide radicals and prevent lipid peroxidation, protein glycosylation, and Na+,K+-ATPase activity in high glucose-treated erythrocytes and hydrogen peroxide-treated monocytes (2) and endothelial cells (3). In bovine endothelial cells, treatment with homocysteine and copper increased extracellular hydrogen peroxide levels. Treatment with pyridoxal or EDTA prevented such increases and enhanced the viability of the cells by supporting apoptosis. 

Jakubowski H, Zhang L, Bardeguez A, Aviv A. Homocysteine thiolactone and protein homocysteinylation in human endothelial cells implications for atherosclerosis. Circ Res 2000 87 45-51. 

Homocysteine decreases the bioavailability of nitrous oxide (NO) via a mechanism involving glutathione peroxidase (37). Tawakol et al. (38) reported that hyperhomocysteinemia is associated with impaired endothelium-dependent vasodilation in humans. Homocysteine impairs the NO synthase pathway both in cell culture (39) and in monkeys with hyperhomocysteinemia, by increasing the levels of asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor (40). Elevation of ADMA may mediate endothelial dysfunction during experimental hyperhomocysteinemia in humans (41). However, Jonasson et al. (42) did not find increased ADMA levels in patients with coronary heart disease and hyperhomocysteinemia, nor did vitamin supplementation have any effect on ADMA levels in spite of substantial plasma tHcy reduction,... 

Mujumdar VS, Aru GM, Tyagi SC. 2001. Induction of oxidative stress by homocysteine impairs endothelial function. J Cell Biochem 82 491-500. 

---