Posted by chris on May 12, 1999 at 09:54:49
I am planning to attend a lecture (presented by a local cardiologist) about risk factors and heart attack. The description of the event goes on to say "a simple blood test to measure one of your amino acid levels can warn you...". Am I right in assuming this is about homocysteine levels? I searched the archives but the only post I could find was from 1997. Has the thinking on this changed any among cardiologists? Apparently the doctor presenting this lecture co-authored an aricle for the New England Journal of Medicine in the past year. Thank you.
Posted by CCF CARDIO MD - CRC on May 12, 1999 at 10:56:28
Thank you for your question. Who is the doctor talking? Here is some information on homocyteine.
Homocysteine is an amino acid that has been linked to coronary artery disease. Excessive quantities of homocysteine were noted to accumulate in the blood of patients with homocystinuria, a rare disease characterized by skeletal, neurological, and vascular abnormalities. From this, a link has been established between more moderate elevations of plasma homocysteine concentrations and atherosclerosis, even in those without any apparent defined genetic trait for homocystinuria.
Plasma homocysteine levels rise with age in both men and women. This may be secondary to decreases in vitamin cofactor levels or coexisting renal impairment, which are common in this age group. Homocysteine concentrations are higher in men than women. This may be due to differences in muscle mass, renal function, essential vitamin cofactors, or even protein intake. Sex hormones may also influence homocysteine metabolism, but this remains speculative at the current time.
Homocysteine concentrations rise with falling renal function. Concentrations are often twice normal in dialysis-dependent patients with end-stage renal disease, but may be substantially higher; levels decrease after dialysis. This increase is likely to be due to impaired metabolism of homocysteine by the kidney or by the liver, whose normal function may be perturbed by the uremic milieu. High plasma homocysteine concentrations have also been observed in patients with psoriasis and acute lymphoblastic leukemia probably reflecting high cell turnover in these disorders.
Homocystinuria has been the paradigm of homocysteine-related atherosclerosis since the early work of Mudd and co-workers. The classical disorder, characterized by complete, or almost complete, absence of cystathionine b-synthase, is rare and occurs in the United States once in 400,000 births. The condition is transmitted in autosomal recessive fashion. Reduced enzyme activity is observed in heterozygotes for the disorder and may be demonstrated by administering a methionine challenge. Markedly elevated plasma homocysteine concentrations are typical and are accompanied by an increase in urinary homocystine. The clinical manifestations include skeletal abnormalities, ocular lens dislocation, and mental retardation. The other major complications of early atherosclerosis and a tendency to thromboembolic events soon became evident after the disorder was first described in a survey of mentally retarded children from Ireland. Plasma homocysteine concentrations may be reduced by dietary methionine restriction or by the administration of vitamin B6, which may protect against vascular complications.
Metabolism of homocysteine requires vitamin B6, vitamin B12, and folate. Vitamin B6 and folate reduce homocysteine concentrations in homocystinuria, and vitamin B6 may reduce the incidence of vascular complications in these patients. In normal subjects and in patients with atherosclerotic vascular disease, homocysteine concentrations may be reduced by folic acid either used alone or else in combination with vitamins B6 or B12 4,5,79. The effect is greatest with folic acid. The effect of vitamin B12 when administered alone is more modest if it occurs at all. Since the effect of these measures on vascular morbidity and mortality have not yet been evaluated, the treatment of patients with vascular disease in whom homocysteine concentrations are high remains speculative although some doctors are treating their patients with higher homocysteine levels with folate.
I hope you find this information useful. Information provided in the heart forum is for general purposes only. Only your physician can provide specific diagnoses and therapies. Please feel free to write back with additional questions.
If you would like to make an appointment at the Cleveland Clinic Heart Center, please call 1-800-CCF-CARE or inquire online by using the Heart Center website at www.ccf.org/heartcenter. The Heart Center website contains a directory of the cardiology staff that can be used to select the physician best suited to address your cardiac problem.
Posted by chris on May 12, 1999 at 14:09:22
Thank you for your response. The advertisement for the lecture says that George Welch, MD is a cardiologist at Maine Cardiology. Within the last year, Dr. Welch co-authored an article for the New England Journal of medicine on the new risk factor for heart attack. It goes on to say that one fourth of all heart atttacks occur in people with no known risk factors. Chris
Posted by CCF CARDIO MD - CRC on May 12, 1999 at 16:07:53
Here is the reference and article you are referring to.
Welch GN. Loscalzo J. Homocysteine and atherothrombosis [see comments]. [Review] [102 refs] New England Journal of Medicine. 338(15):1042-50, 1998 Apr 9. 98181803
In 1969, McCully made the clinical observation linking elevated plasma homocyst(e)ine concentrations with vascular disease.  He reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in two children with elevated plasma homocyst(e)ine concentrations and homocystinuria. On the basis of this observation, he proposed that elevated plasma homocyst(e)ine (hyperhomocyst(e)inemia) can cause atherosclerotic vascular disease. The term "homocyst(e)ine" is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia.
Subsequent investigations have confirmed McCully's hypothesis, and it has recently become clear that hyperhomocyst(e)inemia is an independent risk factor for atherosclerosis and atherothrombosis. Although severe hyperhomocyst(e)inemia is rare, mild hyperhomocyst(e)inemia occurs in approximately 5 to 7 percent of the general population. [2,3] Patients with mild hyperhomocyst(e)inemia have none of the clinical signs of severe hyperhomocyst(e)inemia or homocystinuria and are typically asymptomatic until the third or fourth decade of life when premature coronary artery disease develops, as well as recurrent arterial and venous thrombosis. Abundant epidemiologic evidence has demonstrated that the presence of mild hyperhomocyst(e)inemia is an independent risk factor for atherosclerosis in the coronary, cerebral, and peripheral vasculature (see below). [4,5] Although the molecular mechanism by which homocyst(e)ine or a related metabolite promotes atherothrombosis is unknown, the epidemiologic evidence of the association of hyperhomocyst(e)inemia with atherothrombotic vascular disease is convincing. In this review, we will evaluate the evidence of a relation between elevated plasma homocyst(e)ine concentrations and vascular disease. Potential mechanisms for this effect are also discussed.
Homocyst(e)ine is a sulfur-containing amino acid formed during the metabolism of methionine. Homocyst(e)ine is metabolized by one of two pathways: remethylation and transsulfuration ( Figure 1). In the remethylation cycle, homocyst(e)ine is salvaged by the acquisition of a methyl group in a reaction catalyzed by methionine synthase.  Vitamin B(12)) (cobalamin) is an essential cofactor for methionine synthase, N(5))-methyl-tetrahydrofolate is the methyl donor in this reaction, and N(5)),N(10))-methylenetetrahydrofolate reductase functions as a catalyst in the remethylation process.
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Figure 1. Metabolism of Homocyst(e)ine. Homocysteine is an amino acid intermediate formed during the metabolism of methionine, an essential amino acid derived from dietary protein. It is metabolized by one of two pathways: remethylation and transsulfuration. In the remethylation cycle, homocysteine is salvaged by acquiring a methyl group in a reaction catalyzed by the vitamin B(12))-dependent enzyme methionine synthase. The donor in this reaction is N(5))-methyltetrahydrofolate, and the enzyme N(5)),N(10))-methylenetetrahydrofolate reductase functions as a catalyst in the remethylation cycle. Under conditions in which excess methionine is present or cysteine synthesis is required, homocysteine enters the transsulfuration pathway. In the transsulfuration pathway, homocysteine condenses with serine to form cystathionine in a reaction catalyzed by the vitamin B(6))-dependent rate-limiting enzyme cystathionine (beta)-synthase. Cystathionine is subsequently hydrolyzed to form cysteine, which may in turn be incorporated into glutathione or further metabolized to sulfate and excreted in the urine.
Under conditions in which an excess of methionine is present or cysteine synthesis is required, homocyst(e)ine enters the transsulfuration pathway. In this pathway, homocyst(e)ine condenses with serine to form cystathionine in a reaction catalyzed by the vitamin B(6))-dependent enzyme cystathionine (beta)-synthase.  Cystathionine is subsequently hydrolyzed to form cysteine, which may in turn be incorporated into glutathione or further metabolized to sulfate and excreted in the urine. 
Measurement of Plasma Homocyst(e)inetoctoc
The majority of the clinical studies involving homocyst(e)ine have relied on the measurement of total plasma homocyst(e)ine, which includes homocysteine, mixed disulfides involving homocysteine, homocysteine thiolactone, free homocysteine, and protein-bound homocysteine. Protein-bound (i.e., disulfide-linked) homocysteine accounts for 70 to 80 percent of the total pool.  Normal total plasma homocyst(e)ine concentrations range from 5 to 15 micromol per liter in the fasting state. [6,9] Kang and coworkers have classified hyperhomocyst(e)inemia as moderate (homocyst(e)ine concentration, 15 to 30 micromol per liter), intermediate (>30 to 100 micromol per liter), and severe (>100 micromol per liter)  on the basis of concentrations measured during fasting.
An oral dose of methionine (100 mg per kilogram of body weight) can be given to persons with suspected hyperhomocyst(e)inemia who have normal homocyst(e)ine concentrations during fasting.  Plasma homocyst(e)ine concentrations are determined before the methionine challenge and between four and eight hours afterward.  Hyperhomocyst(e)inemia is considered to be present if the homocyst(e)ine concentration after methionine challenge is more than 2 SD above the mean.  The prognostic value of the methionine-challenge test has recently been criticized : in persons with the thermolabile variant of N(5)),N(10))-methylenetetrahydrofolate reductase, there was only a weak association between plasma homocyst(e)ine concentrations after methionine challenge and premature coronary heart disease (odds ratio, 1.7; P = 0.12), whereas there was a significant association between plasma homocyst(e)ine concentrations during fasting and premature coronary heart disease (odds ratio, 2.0; P = 0.04). These authors concluded that this enzyme regulates basal homocyst(e)ine concentrations, and thus, its activity cannot be adequately assessed by a methionine-challenge test. By contrast, enzymes in the transsulfuration pathway are responsible for reversing transient, postprandial increases in the homocyst(e)ine concentration, and their activities can be evaluated by a methionine-challenge test.
Genetic Defects in Homocysteine Metabolismtoctoc
Elevations in plasma homocyst(e)ine are typically caused either by genetic defects in the enzymes involved in homocysteine metabolism or by nutritional deficiencies in vitamin cofactors. Homocystinuria and severe hyperhomocyst(e)inemia are caused by rare inborn errors of metabolism resulting in marked elevations of plasma and urine homocyst(e)ine concentrations. Cystathionine (beta)-synthase deficiency is the most common genetic cause of severe hyperhomocyst(e)inemia. The homozygous form of this disease - congenital homocystinuria - can be associated with plasma homocyst(e)ine concentrations of up to 400 micromol per liter during fasting.  The homozygous trait is rare (occurring in 1 in 200,000 births), and clinical manifestations include ectopia lentis, skeletal deformities, mental retardation, thromboembolism, and severe, premature atherosclerosis.  Atherothrombotic complications frequently develop in young adulthood in homozygotes and are often fatal, as first shown in a study by Carey and colleagues as early as 1968.  Mudd and colleagues  have estimated that approximately 50 percent of untreated patients with homocystinuria will have a thromboembolic event before the age of 30 and that overall, the disease-related mortality is approximately 20 percent. Heterozygotes typically have much less marked hyperhomocyst(e)inemia, with plasma homocyst(e)ine concentrations in the range of 20 to 40 micromol per liter, approximately two to four times greater than the normal concentration of homocyst(e)ine in plasma. [13,15-17]
A homozygous deficiency of N(5)),N(10))-methylenetetrahydrofolate reductase, the enzyme involved in the vitamin B(12))-dependent remethylation of homocysteine to methionine, may also lead to severe hyperhomocyst(e)inemia.  Patients with this type of deficiency tend to have a worse prognosis than those with cystathionine (beta)-synthase deficiency, in part because of the complete lack of effective therapy. [19,20] In addition, Kang and colleagues  have reported a thermolabile variant of N(5)),N(10))-methylenetetrahydrofolate reductase that is caused by a point mutation (C677T) in the coding region for the N(5)),N(10))-methylenetetrahydrofolate binding site, leading to the substitution of valine for alanine.  This mutation was found in 38 percent of French Canadians and 5 to 15 percent of the general population in Canada and correlated with elevated plasma homocyst(e)ine concentrations. [22,23] Although this variant of the N(5)),N(10))-methylenetetrahydrofolate reductase gene is quite common, it does not appear to be a significant, independent risk factor for atherothrombotic vascular disease. [24-26] Persons who are homozygous for this mutation appear to have an exaggerated hyperhomocyst(e)inemic response to the depletion of folic acid and with folic acid depletion may be at increased risk for vascular disease.  Other abnormalities of the remethylation cycle that are associated with hyperhomocyst(e)inemia include methionine synthase deficiency and disorders of vitamin B(12)) metabolism that impair methionine synthase activity.
Nutritional Deficiencies Causing Hyperhomocyst(e)inemiatoctoc
Nutritional deficiencies in the vitamin cofactors (folate, vitamin B(12)), and vitamin B(6))) required for homocysteine metabolism may promote hyperhomocyst(e)inemia. Markedly elevated homocyst(e)ine concentrations have been observed in patients with nutritional deficiencies of the essential cofactor vitamin B(12))  and the cosubstrate folate. [28,29] Negative correlations between serum vitamin B(12)), folate, and vitamin B(6)) concentrations and plasma homocyst(e)ine concentrations have been observed in normal subjects.  Selhub and colleagues  have suggested that inadequate plasma concentrations of one or more B vitamins are contributing factors in approximately two thirds of all cases of hyperhomocyst(e)inemia. Vitamin supplementation can normalize high homocyst(e)ine concentrations (see below); however, it remains to be determined whether normalizing homocyst(e)ine concentrations will improve cardiovascular morbidity and mortality.
Other Causes of Hyperhomocyst(e)inemiatoctoc
A number of other factors influence homocyst(e)ine metabolism, including several disease states and medications. Plasma homocyst(e)ine concentrations increase with elevations in creatinine and are typically elevated in chronic renal failure, often approaching concentrations that are up to four times the normal value. [31,32] Although plasma homocyst(e)ine concentrations often decrease after dialysis,  it is unclear whether the elevation in homocyst(e)ine observed in end-stage renal disease is due to impaired metabolism or to reduced excretion. The presence of elevated plasma homocyst(e)ine concentrations may partially explain the observed acceleration of atherosclerosis in end-stage renal disease.
A number of reports have linked hyperhomocyst(e)inemia to hypothyroidism,  suggesting a potential mechanism for the higher incidence of vascular disease observed in patients with hypothyroidism. Hyperhomocyst(e)inemia has also been reported in patients with pernicious anemia, and elevated plasma homocyst(e)ine concentrations are helpful in diagnosing this disorder. In one study of 434 patients with cobalamin deficiency, approximately 96 percent had serum homocyst(e)ine concentrations that were more than 3 SD above the mean.  It is unclear whether these patients are at increased risk for vascular events.
Elevated homocyst(e)ine concentrations have been reported in association with several types of carcinoma, including breast, ovarian, and pancreatic cancer.  Transformed cells in culture are unable to use homocyst(e)ine, and it has been suggested that proliferating tumor cells may also be incapable of metabolizing endogenous homocysteine. [2,34] In addition, acute lymphoblastic leukemia is associated with marked elevations in plasma homocyst(e)ine; after chemotherapy for this disorder, homocyst(e)ine concentrations decrease dramatically. [34,35]
Several drugs and toxins increase plasma homocyst(e)ine concentrations. Methotrexate depletes folate, the cosubstrate for methionine synthase, and causes a transient increase in plasma homocyst(e)ine concentrations. [2,36] Phenytoin also interferes with folate metabolism and may cause mild hyperhomocyst(e)inemia. [2,36] Theophylline, a phosphodiesterase inhibitor, may cause hyperhomocyst(e)inemia by antagonizing the synthesis of pyridoxal phosphate (vitamin B(6))).  Cigarette smoking also interferes with the synthesis of pyridoxal phosphate,  and it has recently been reported that smokers have significantly lower pyridoxal phosphate concentrations than nonsmokers.  These results suggest another important mechanism whereby smoking may promote atherogenesis.
Association between Hyperhomocyst(e)inemia and Atherosclerosistoctoc
Since McCully hypothesized that elevated plasma homocyst(e)ine concentrations could cause atherosclerosis, abundant epidemiologic evidence from more than 20 case-control and cross-sectional studies involving over 2000 patients [36,40] has validated this relation. Boers and colleagues  screened 75 patients with premature atherosclerotic vascular disease for hyperhomocyst(e)inemia using methionine challenge and found that nearly one third of all patients with cerebrovascular disease and peripheral vascular disease had hyperhomocyst(e)inemia. Clarke and colleagues  subsequently measured homocyst(e)ine concentrations after methionine loading in a cohort of men with premature vascular disease and normal controls and demonstrated that 42 percent of patients with cerebrovascular disease, 28 percent of patients with peripheral vascular disease, and 30 percent of patients with coronary artery disease had hyperhomocyst(e)inemia. Clarke et al. also found that the relative risk of coronary artery disease in patients with hyperhomocyst(e)inemia was approximately 24 times that in controls.
Two large, prospective studies have assessed the risk of coronary artery disease in patients with hyperhomocyst(e)inemia. In the Physicians' Health Study, 14,916 male physicians without known atherosclerosis had an initial homocyst(e)ine measurement and were prospectively followed for an average of five years.  Men with plasma homocyst(e)ine concentrations that were 12 percent above the upper limit of normal had approximately a threefold increase in the risk of myocardial infarction, as compared with those with lower levels, even after correction for other risk factors. The authors estimated that 7 percent of the 271 observed myocardial infarctions could be attributed to hyperhomocyst(e)inemia. The prospective design of the study eliminated the possibility that atherosclerosis itself may have altered homocyst(e)ine concentrations. The prospective Tromso study  reported similar results, and several other prospective studies have consistently indicated that hyperhomocyst(e)inemia is an independent risk factor for vascular disease. [44-46]
Selhub and colleagues  have recently demonstrated that the prevalence of carotid-artery stenosis increases with increasing plasma concentrations of homocyst(e)ine. In a cross-sectional study of 1041 elderly subjects in the Framingham Heart Study, they found a strong association between elevated homocyst(e)ine concentrations and occlusive vascular disease that remained even after adjustment for other conventional coronary risk factors. There was a graded, rather than a threshold, relation between plasma homocyst(e)ine and the risk of carotid stenosis. The risk of carotid stenosis was increased even at lower plasma concentrations of homocyst(e)ine (between 11.4 and 14.3 micromol per liter) that had previously been considered to be normal. Malinow and colleagues  reported similar results in an earlier study. A graded response has also been demonstrated between homocyst(e)ine concentrations and the risk of coronary artery disease or cerebrovascular accident. [5,49-51]
Graham and coworkers  recently measured plasma homocyst(e)ine concentrations in 750 patients with atherosclerosis and 800 normal subjects. There was a statistically significant difference in plasma homocyst(e)ine concentrations during fasting between patients and controls (11.25 micromol per liter vs. 9.73 micromol per liter, P<0.001), and a methionine challenge revealed that an additional 27 percent of patients had hyperhomocyst(e)inemia. Interestingly, an elevated plasma homocyst(e)ine concentration conferred an independent risk of vascular disease similar to that of smoking or hypercholesterolemia and also had a multiplicative effect on risk among cigarette smokers and patients with hypertension.  The authors therefore suggested that controlling hypertension and smoking may be particularly important in patients with hyperhomocyst(e)inemia.
Nygard and colleagues  recently reported a prospective study involving 587 patients with angiographically documented coronary artery disease. Base-line homocyst(e)ine measurements were obtained, and patients were followed for a median of 4.6 years, during which time 10.9 percent of them died. These investigators found a strong, graded association between plasma homocyst(e)ine concentrations and overall mortality. The relation between homocyst(e)ine and mortality was strongest for total homocyst(e)ine concentrations above 15 micromol per liter. The adjusted mortality ratio was 1.6 for patients with homocyst(e)ine concentrations of 15 micromol per liter, as compared with those with values of 10 micromol per liter. However, total homocyst(e)ine concentrations were only weakly associated with the extent of coronary artery disease in this study. This study and other key studies designed to evaluate the relation between plasma homocyst(e)ine concentrations and atherothrombotic risk are summarized in Table 1.
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Table 1. Major Observational Studies of Homocyst(e)ine as a Risk Factor for Atherothrombotic Disease.
In a recent meta-analysis, Boushey and colleagues  estimated that 10 percent of the risk of coronary artery disease in the general population is attributable to homocyst(e)ine. They reported that an increase of 5 micromol per liter in the plasma homocyst(e)ine concentration raises the risk of coronary artery disease by as much as an increase of 20 mg per deciliter (0.52 mmol per liter) in the cholesterol concentration. They suggested that increasing folate consumption by approximately 200 microg per day would reduce total homocyst(e)ine concentrations by approximately 4 micromol per liter, a reduction that could potentially have a major effect on cardiovascular mortality. Randomized clinical trials will be necessary to demonstrate the clinical utility of this strategy. Importantly, the current fortification program will increase folate consumption by approximately half this amount, and it remains to be seen whether this dietary supplementation of folate will affect the prevalence of coronary heart disease in the general population.
Den Heijer and colleagues  have demonstrated that mild hyperhomocyst(e)inemia is also an independent risk factor for venous thromboembolism. They found a marked increase in the risk of venous thrombosis at the highest plasma homocyst(e)ine concentrations. A plasma homocyst(e)ine concentration of more than 22 micromol per liter increased the matched odds ratio for deep venous thrombosis to 4.0. It is unknown whether homocyst(e)ine-lowering therapy reduces the risk of venous thrombosis in patients with such high concentrations. Recently, Ridker and associates  showed that the combination of hyperhomocyst(e)inemia and factor V Leiden further increases the relative risk of venous thromboembolism up to 3.6-fold.
Treatment of Hyperhomocyst(e)inemiatoctoc
The treatment of hyperhomocyst(e)inemia varies with the underlying cause; however, vitamin supplementation (with folic acid, pyridoxine, and vitamin B(12))) is generally effective in reducing homocyst(e)ine concentrations. The minimal effective doses of folic acid and pyridoxine have not yet been determined. In most patients, small doses of folate (1 to 5 mg per day) rapidly decrease homocyst(e)ine concentrations.  Folic acid alone, folic acid combined with vitamins B(12)) and B(6)), and vitamins B(6)) and B(12)) have all been shown to reduce homocyst(e)ine concentrations.  Normalization of the plasma homocyst(e)ine concentration usually occurs within four to six weeks after the initiation of therapy, but may occur in as little as two weeks. Interestingly, the reduction in mortality from cardiovascular causes since 1960 has been correlated with the increase in vitamin B(6)) supplementation in the food supply. 
Pathophysiologic Mechanisms of Hyperhomocyst(e)inemiatoctoc
Experimental evidence suggests that the atherogenic propensity associated with hyperhomocyst(e)inemia results from endothelial dysfunction and injury followed by platelet activation and thrombus formation. Studies in humans and animals demonstrate that homocyst(e)ine-induced atherosclerosis is characterized by substantial platelet accumulation and platelet-rich thrombus formation in areas of endothelial injury. [59-61] Harker and colleagues have proposed that homocyst(e)ine-induced endothelial injury exposes the subendothelial matrix, which in turn leads to platelet activation. [59,60] Lentz and colleagues  have demonstrated that diet-induced hyperhomocyst(e)inemia in primates leads to impaired vasomotor regulation in vivo and endothelial antithrombotic function ex vivo. These findings are supported by the work of Celermajer and colleagues,  who demonstrated impaired endothelium-dependent vasodilation, and also by van den Berg and colleagues,  who demonstrated impaired endothelial anticoagulant function in young patients with hyperhomocyst(e)inemia and peripheral vascular disease. Although the exact mechanism of endothelial dysfunction is unknown, there is growing evidence that homocyst(e)ine exerts its effects by promoting oxidative damage.
Homocyst(e)ine is rapidly auto-oxidized when added to plasma, forming homocystine, mixed disulfides, and homocysteine thiolactone ( Figure 2). [65-67] Potent reactive oxygen species, including superoxide and hydrogen peroxide, are produced during the auto-oxidation of homocyst(e)ine, and hydrogen peroxide (along with the hydroxyl radical), in particular, has been implicated in the vascular toxicity of hyperhomocyst(e)inemia.  There is extensive evidence that homocyst(e)ine-induced endothelial-cell injury in vitro is largely due to the generation of hydrogen peroxide. [69-71] Harker and colleagues  have proposed that homocyst(e)ine-induced endothelial-cell injury mediated by hydrogen peroxide exposes the underlying matrix and smooth-muscle cells, which in turn proliferate and promote the activation of platelets and leukocytes.
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Figure 2. Postulated Adverse Vascular Effects of Homocyst(e)ine. The postulated effects involve oxidative damage to vascular endothelial cells and increased proliferation of vascular smooth-muscle cells after oxidative metabolism of homocysteine to homocystine and homocysteine thiolactone. Oxidative modification of low-density lipoprotein (LDL) promotes the formation of foam cells, which in turn yields another source of reactive oxygen species.
Auto-oxidation of homocyst(e)ine produces other cytotoxic reactive oxygen species, including the superoxide anion radical and hydroxyl radical. [72,73] Superoxide-dependent formation of the hydroxyl radical has been shown to initiate lipid peroxidation,  an effect that occurs at the level of the endothelial plasma membrane and within lipoprotein particles. [74,75] Homocyst(e)ine auto-oxidation has been shown to support the oxidation of low-density lipoprotein through the generation of the superoxide anion radical. [74,76]
Although the precise molecular mechanism is unknown, homocyst(e)ine causes endothelial dysfunction at several levels. Homocyst(e)ine alters the normal antithrombotic phenotype of the endothelium by enhancing the activities of factor XII  and factor V  and depressing the activation of protein C.  Homocyst(e)ine also inhibits the expression of thrombomodulin,  induces the expression of tissue factor,  and suppresses the expression of heparan sulfate by the endothelium.  All of these effects ultimately facilitate the formation of thrombin and create a prothrombotic environment.
The production of endothelial-derived nitric oxide is also adversely affected by homocyst(e)ine. Our group  has previously shown that normal endothelial cells detoxify homocyst(e)ine by releasing nitric oxide, which combines with homocysteine in the presence of oxygen to form S-nitroso-homocysteine. Nitrosation of the sulfhydryl group of homocysteine inhibits sulfhydryl-dependent generation of hydrogen peroxide.  S-nitroso-homocysteine is also a potent platelet inhibitor and vasodilator.  This protective effect of nitric oxide is eventually compromised as long-term exposure to hyperhomocyst(e)inemia damages the endothelium sufficiently to limit nitric oxide production. Impaired endothelial production of nitric oxide leaves the endothelium vulnerable to unopposed homocyst(e)ine-mediated oxidative injury.  Homocyst(e)ine may also decrease the bioavailability of nitric oxide by impairing its synthesis. [68,75] Homocyst(e)ine promotes lipid peroxidation, which may subsequently decrease the expression of endothelial nitric oxide synthase and directly degrade nitric oxide. [84-86] Our group has recently shown that homocysteine (but not cysteine) suppresses the expression of cellular glutathione peroxidase by endothelial cells, and this effect promotes lipid peroxidation by the reactive oxygen species elaborated during the oxidation of homocysteine. 
In addition to promoting atherosclerosis through endothelial injury or dysfunction, homocyst(e)ine is also a potent mitogen for vascular smooth-muscle cells. Harker and colleagues  demonstrated that infusion of homocyst(e)ine into baboons results in the formation of atheromata. Exposure to homocyst(e)ine leads to a marked increase in vascular smooth-muscle proliferation in vitro, an effect that is due in part to an increase in the expression of messenger RNA of cyclin D1 and cyclin A.  Tsai and coworkers  have proposed that homocyst(e)ine promotes atherogenesis specifically by inducing the proliferation of vascular smooth-muscle cells.
We have recently demonstrated that homocyst(e)ine increases nitric oxide production in vascular smooth-muscle cells by activating the transcription factor NF-(kappa)B.  It appears that NF-(kappa)B is activated by a homocyst(e)ine-generated reactive oxygen species.  Since NF-(kappa)B/rel activity is essential for the proliferation of vascular smooth-muscle cells,  these data suggest that homocyst(e)ine-mediated activation of NF-(kappa)B contributes to the mitogenic effect of homocyst(e)ine.
Homocyst(e)ine also directly damages the vascular matrix by affecting the biochemical and biosynthetic functions of vascular cells. Homocysteine thiolactone, a highly reactive anhydrous byproduct of homocysteine oxidation, combines with low-density lipoprotein to form aggregates that are taken up by intimal macrophages and incorporated into foam cells within nascent atheromatous plaques.  There is, however, some doubt that the thiolactone can form in sufficient concentrations in vivo to evoke these effects. Recently, Jakubowski showed that cells deficient in cystathionine (beta)-synthase produce more homocysteine thiolactone in culture than normal cells and that the thiolactone is incorporated into cellular and secreted proteins through lysine acylation by the activated carboxyl group of the thiolactone.  McCully  has suggested that in this microenvironment homocysteine thiolactone facilitates the conversion of mitochondrial thioretinaco ozonide to thioco, thereby impairing oxidative phosphorylation and promoting the proliferation and fibrosis of smooth muscles. [95-97] This homocyst(e)ine-induced disturbance in oxidative metabolism also leads to overproduction of oxidative radicals that subsequently induce intimal injury, activate elastase, and increase calcium deposition. [96,98] Homocyst(e)ine may also contribute to the deposition of sulfated glycosaminoglycan in the matrix; it appears that the sulfur group of homocysteine thiolactone is incorporated into phosphoadenosine phosphosulfate, which ultimately leads to the formation of sulfated glycosaminoglycans. 
The recently observed multiplicative increase in the risk of vascular disease in the presence of traditional risk factors and hyperhomocyst(e)inemia  may in part be related to the effect of homocyst(e)ine on lipid peroxidation. The vascular cytotoxicity of oxidized low-density lipoprotein has been linked to its content of lipid peroxidation products. [99,100] Homocyst(e)ine increases the formation of highly atherogenic oxycholesterols, increases lipid peroxidation, and increases the oxidation of low-density lipoprotein in vitro. [101,102] These observations suggest a potential role for antioxidant therapy in ameliorating homocyst(e)ine-dependent oxidative vascular injury; however, this therapeutic approach has not yet been tested in prospective clinical trials.
Multiple prospective and case-control studies have shown that a moderately elevated plasma homocysteine concentration is an independent risk factor for atherothrombotic vascular disease. Homocysteine concentrations are consistently higher in patients with peripheral, cerebrovascular, and coronary artery disease than in those without such diseases. Homocyst(e)ine promotes atherothrombogenesis by a variety of mechanisms; however, it is not yet clear whether homocysteine itself or a related metabolite or cofactor is primarily responsible for the atherothrombogenic effects of hyperhomocyst(e)inemia in vivo. Before advocating widespread screening of patients with atherosclerotic vascular disease, we must have a clearer understanding of the clinical efficacy of potential therapeutic interventions. Vitamin supplementation decreases or even normalizes plasma homocyst(e)ine concentrations in most cases. Prospective, randomized clinical trials, however, will be necessary to determine the effect of vitamin supplementation on cardiovascular morbidity and mortality.
Supported in part by grants (HL58976, HL53919, HL55993, and HL48743) from the National Institutes of Health and by a Merit Review Award from the Department of Veterans Affairs.
We are indebted to Adrian Zai for invaluable assistance with the artwork and to Dr. Gilbert R. Upchurch, Jr., for critical review of the manuscript.
1. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969;56:111-28. [Medline Link] [Context Link]
2. Ueland PM, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med 1989;114:473-501. [Medline Link] [Context Link]
3. McCully KS. Homocysteine and vascular disease. Nat Med 1996;2:386-9. [Medline Link] [Context Link]
4. Kang SS, Wong PW, Malinow MR. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Ann Rev Nutr 1992;12:279-98. [Medline Link] [Context Link]
5. Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268:877-81. [Medline Link] [Context Link]
6. Ueland PM, Refsum H, Stabler SP, Malinow MR, Andersson A, Allen RH. Total homocysteine in plasma or serum: methods and clinical applications. Clin Chem 1993;39:1764-79. [Medline Link] [Context Link]
7. Finkelstein JD, Martin JJ, Harris **. Methionine metabolism in mammals: the methionine-sparing effect of cystine. J Biol Chem 1988;263:11750-4. [Medline Link] [Context Link]
8. Ueland PM. Homocysteine species as components of plasma redox thiol status. Clin Chem 1995;41:340-2. [Medline Link] [Context Link]
9. Jacobsen DW, Gatautis VJ, Green R, et al. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem 1994;40:873-81. [Medline Link] [Context Link]
10. Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine/homocysteine metabolism in premature vascular disease: its occurrence, cofactor therapy, and enzymology. Arterioscler Thromb 1993;13:1253-60. [Medline Link] [Context Link]
11. Gallagher PM, Meleady R, Shields DC, et al. Homocysteine and risk of premature coronary disease: evidence for a common gene mutation. Circulation 1996;94:2154-8. [Medline Link] [Context Link]
12. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 7th ed. Vol. 1. New York: McGraw-Hill, 1995:1279-327. [Context Link]
13. Carey MC, Donovan DE, FitzGerald O, McAuley FD. Homocystinuria. I. A clinical and pathological study of nine subjects in six families. Am J Med 1968;45:7-25. [Medline Link] [Context Link]
14. Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine (beta)-synthase deficiency. Am J Hum Genet 1985;37:1-31. [Medline Link] [Context Link]
15. Malinow MR, Kang SS, Taylor LM, et al. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation 1989;79:1180-8. [Medline Link] [Context Link]
16. Coull BM, Malinow MR, Beamer N, Sexton G, Nordt F, de Garmo P. Elevated plasma homocyst(e)ine concentration as a possible independent risk factor for stroke. Stroke 1990;21:572-6. [Medline Link] [Context Link]
17. Malinow MR, Sexton G, Averbuch M, Grossman M, Wilson O, Upson B. Homocyst(e)ine in daily practice: levels in coronary heart disease. Coronary Artery Dis 1990;2:4-12. [Context Link]
18. Mudd SH, Uhlendorf BW, Freeman JM, Finkelstein JD, Shih VE. Homocystinuria associated with decreased methylenetetrahydrofolate reductase activity. Biochem Biophys Res Commun 1972;46:905-12. [Medline Link] [Context Link]
19. Erbe RW. Inborn errors of folate metabolism. In: Blakely RL, Whitehead VM, eds. Folate and pterins: nutritional, pharmacological, and physiological aspects. New York: Marcel Dekker, 1986:413-25. [Context Link]
20. D'Angelo A, Selhub J. Homocysteine and thrombotic disease. Blood 1997;90:1-11. [Medline Link] [Context Link]
21. Kang SS, Zhou J, Wong PWK, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 1988;43:414-21. [Medline Link] [Context Link]
22. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111-3. [Medline Link] [Context Link]
23. Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677 given to Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997;77:818-21. [Medline Link] [Context Link]
24. Ma J, Stampfer MJ, Hennekens CH, et al. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation 1996;94:2410-6. [Fulltext Link] [Medline Link] [Context Link]
25. van Bockxmeer FM, Mamotte CD, Vasikaran SD, Taylor RR. Methylenetetrahydrofolate reductase gene and coronary artery disease. Circulation 1997;95:21-3. [Fulltext Link] [Context Link]
26. Deloughery TG, Evans A, Sadeghi A, et al. Common mutation in methylenetetrahydrofolate reductase: correlation with homocysteine metabolism and late-onset vascular disease. Circulation 1996;94:3074-8. [Fulltext Link] [Medline Link] [Context Link]
27. Brattstrom L, Israelsson B, Lindgarde F, Hultberg B. Higher total plasma homocysteine in vitamin B(12)) deficiency than in heterozygosity for homocystinuria due to cystathionine (beta)-synthase deficiency. Metabolism 1988;37:175-8. [Medline Link] [Context Link]
28. Kang SS, Wong PWK, Norusis M. Homocysteinemia due to folate deficiency. Metabolism 1987;36:458-62. [Medline Link] [Context Link]
29. Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest 1988;81:466-74. [Medline Link] [Context Link]
30. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693-8. [Fulltext Link] [Medline Link] [Context Link]
31. Wilcken DE, Gupta VJ. Sulphur containing amino acids in chronic renal failure with particular reference to homocystine and cysteine-homocysteine mixed disulphide. Eur J Clin Invest 1979;9:301-7. [Medline Link] [Context Link]
32. Chauveau P, Chadefaux B, Coude M, et al. Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int Suppl 1993;41:S72-S77. [Medline Link] [Context Link]
33. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinants for diagnosing cobalamin and folate deficiencies. Am J Med 1994;96:239-46. [Medline Link] [Context Link]
34. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 1996;27:517-27. [Medline Link] [Context Link]
35. Refsum H, Wesenberg F, Ueland PM. Plasma homocysteine in children with acute lymphoblastic leukemia: changes during a chemotherapeutic regimen including methotrexate. Cancer Res 1991;51:828-35. [Medline Link] [Context Link]
36. Ueland PM, Refsum H, Brattstrom L. Plasma homocysteine and cardiovascular disease. In: Francis RB Jr, ed. Atherosclerotic cardiovascular disease, hemostasis, and endothelial function. New York: Marcel Dekker, 1992:183-236. [Context Link]
37. Ubbink JB, van der Merwe A, Delport A, et al. The effect of a subnormal vitamin B(6)) status on homocysteine metabolism. J Clin Invest 1996;98:177-84. [Fulltext Link] [Medline Link] [Context Link]
38. Nygard O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile: the Hordaland Homocysteine Study. JAMA 1995;274:1526-33. [Fulltext Link] [Medline Link] [Context Link]
39. Vermaak WJ, Ubbink JB, Barnard HC, Potgieter GM, van Jaarsveld H, Groenewald AJ. Vitamin B(6)) nutrition status and cigarette smoking. Am J Clin Nutr 1990;51:1058-61. [Medline Link] [Context Link]
40. Stampfer MJ, Malinow MR. Can lowering homocysteine levels reduce cardiovascular risk? N Engl J Med 1995;332:328-9. [Fulltext Link] [Medline Link] [Context Link]
41. Boers GHJ, Smals AGH, Trijbels FJM, et al. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med 1985;313:709-15. [Medline Link] [Context Link]
42. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324:1149-55. [Medline Link] [Context Link]
43. Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE. Serum total homocysteine and coronary heart disease. Int J Epidemiol 1995;24:704-9. [Medline Link] [Context Link]
44. Alfthan G, Pekkanen J, Jauhiainen M, et al. Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 1994;106:9-19. [Medline Link] [Context Link]
45. Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke 1994;25:1924-30. [Medline Link] [Context Link]
46. Taylor LM Jr, DeFrang RD, Harris EJ Jr, Porter JM. The association of elevated plasma homocyst(e)ine with progression of symptomatic peripheral arterial disease. J Vasc Surg 1991;13:128-36. [Medline Link] [Context Link]
47. Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995;332:286-91. [Fulltext Link] [Medline Link] [Context Link]
48. Malinow MR, Nieto FJ, Szklo M, Chambless LE, Bond G. Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults: the Atherosclerosis Risk in Communities Study. Circulation 1993;87:1107-13. [Fulltext Link] [Medline Link] [Context Link]
49. Genest JJ Jr, McNamara JR, Upson B, et al. Prevalence of familial hyperhomocyst(e)inemia in men with premature coronary artery disease. Arterioscler Thromb 1991;11:1129-36. [Medline Link] [Context Link]
50. Pancharuniti N, Lewis CA, Sauberlich HE, et al. Plasma homocyst(e)ine, folate, and vitamin B(12)) concentrations and risk for early-onset coronary artery disease. Am J Clin Nutr 1994;59:940-8. [Medline Link] [CINAHL Link] [Context Link]
51. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995;346:1395-8. [Fulltext Link] [Medline Link] [Context Link]
52. Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease: the European Concerted Action Project. JAMA 1997;277:1775-81. [Fulltext Link] [Medline Link] [Context Link]
53. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-6. [Fulltext Link] [Medline Link] [Context Link]
54. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57. [Fulltext Link] [Medline Link] [Context Link]
55. den Heijer M, Kostor T, Blom HJ, et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996;334:759-62. [Fulltext Link] [Medline Link] [Context Link]
56. Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 1997;95:1777-82. [Fulltext Link] [Medline Link] [Context Link]
57. Brattstrom LE, Israelsson B, Jeppsson JO, Hultberg BL. Folic acid - an innocuous means to reduce plasma homocysteine. Scand J Clin Lab Invest 1988;48:215-21. [Medline Link] [Context Link]
58. Saltzman E, Mason JB, Jacques PF, et al. B vitamin supplementation lowers homocysteine levels in heart disease. Clin Res 1994;42:172A. abstract. [Context Link]
59. Harker LA, Slichter SJ, Scott CR, Ross R. Homocystinemia: vascular injury and arterial thrombosis. N Engl J Med 1974;291:537-43. [Medline Link] [Context Link]
60. Harker LA, Ross R, Slichter SJ, Scott CR. Homocystine-induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis. J Clin Invest 1976;58:731-41. [Medline Link] [Context Link]
61. James TN. The spectrum of diseases of small coronary arteries and their physiologic consequences. J Am Coll Cardiol 1990;15:763-74. [Medline Link] [Context Link]
62. Lentz SR, Sobey CG, Piegors DJ, et al. Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest 1996;98:24-9. [Fulltext Link] [Medline Link] [Context Link]
63. Celermajer DS, Sorensen K, Ryalls M, et al. Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. J Am Coll Cardiol 1993;22:854-8. [Medline Link] [Context Link]
64. van den Berg M, Boers GH, Franken DG, et al. Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. Eur J Clin Invest 1995;25:176-81. [Medline Link] [Context Link]
65. Velury S, Howell SB. Measurement of plasma thiols after derivatization with monobromobimane. J Chromatogr 1988;424:141-6. [Medline Link] [Context Link]
66. Stamler JS, Osborne JA, Jaraki O, et al. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 1993;91:308-18. [Fulltext Link] [Medline Link] [Context Link]
67. Andersson A, Lindgren A, Hultberg B. Effect of thiol oxidation and thiol export from erythrocytes on determination of redox status of homocysteine and other thiols in plasma from healthy subjects and patients with cerebral infarction. Clin Chem 1995;41:361-6. [Medline Link] [Context Link]
68. Welch GN, Upchurch GR Jr, Loscalzo J. Hyperhomocyst(e)inemia and atherothrombosis. Ann N Y Acad Sci 1997;811:48-58. [Medline Link] [Context Link]
69. Wall RT, Harlan JM, Harker LA, Striker GE. Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res 1980;18:113-21. [Medline Link] [Context Link]
70. de Groot PG, Willems C, Boers GH, Gonsalves MD, van Aken WG, van Mourik JA. Endothelial cell dysfunction in homocystinuria. Eur J Clin Invest 1983;13:405-10. [Medline Link] [Context Link]
71. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1986;77:1370-6. [Medline Link] [Context Link]
72. Misra HP. Generation of superoxide free radical during the autooxidation of thiols. J Biol Chem 1974;249:2151-5. [Medline Link] [Context Link]
73. Rowley DA, Halliwell B. Superoxide-dependent formation of hydroxyl radicals in the presence of thiol compounds. FEBS Lett 1982;138:33-6. [Medline Link] [Context Link]
74. Heinecke JW. Superoxide-mediated oxidation of low density lipoprotein by thiols. In: Cerutti PA, Fridovich I, McCord JM, eds. Oxy-radicals in molecular biology and pathology. New York: Alan R. Liss, 1988:443-57. [Context Link]
75. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 1996;98:5-7. [Fulltext Link] [Medline Link] [Context Link]
76. Heinecke JW, Rosen H, Suzuki LA, Chait A. The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J Biol Chem 1987;262:10098-103. [Medline Link] [Context Link]
77. Ratnoff OD. Activation of Hageman factor by L-homocystine. Science 1968;162:1007-9. [Medline Link] [Context Link]
78. Rodgers GM, Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 1986;77:1909-16. [Medline Link] [Context Link]
79. Rodgers GM, Conn MT. Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 1990;75:895-901. [Medline Link] [Context Link]
80. Lentz SR, Sadler JE. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 1991;88:1906-14. [Medline Link] [Context Link]
81. Fryer RH, Wilson BD, Gubler DB, Fitzgerald LA, Rodgers GM. Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb 1993;13:1327-33. [Medline Link] [Context Link]
82. Nishinaga M, Ozawa T, Shimada K. Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells. J Clin Invest 1993;92:1381-6. [Fulltext Link] [Medline Link] [Context Link]
83. Stamler JS, Simon DI, Osborne JA, et al. S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc Natl Acad Sci U S A 1992;89:444-8. [Medline Link] [Context Link]
84. Chin JH, Azhar S, Hoffman BB. Inactivation of endothelial derived relaxing factor by oxidized lipoproteins. J Clin Invest 1992;89:10-8. [Medline Link] [Context Link]
85. Liao JK, Shin WS, Lee WY, Clark SL. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 1995;270:319-24. [Medline Link] [Context Link]
86. Blom HJ, Kleinveld HA, Boers GH, et al. Lipid peroxidation and susceptibility of low-density lipoprotein to in vitro oxidation in hyperhomocysteinaemia. Eur J Clin Invest 1995;25:149-54. [Medline Link] [Context Link]
87. Upchurch GR Jr, Welch GN, Fabian AJ, et al. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 1997;272:17012-7. [Medline Link] [Context Link]
88. Harker LA, Harlan JM, Ross R. Effect of sulfinpyrazone on homocysteine-induced endothelial injury and arteriosclerosis in baboons. Circ Res 1983;53:731-9. [Medline Link] [Context Link]
89. Tsai J-C, Perrella MA, Yoshizumi M, et al. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci U S A 1994;91:6369-73. [Medline Link] [Context Link]
90. Tsai JC, Wang H, Perrella MA, et al. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells. J Clin Invest 1996;97:146-53. [Medline Link] [Context Link]
91. Welch GN, Upchurch GR Jr, Farivar RS, et al. Homocysteine-induced nitric oxide production in vascular smooth muscle cells by NF-(kappa)B dependent transcriptional activation of Nos2. Proc Am Assoc Phys 1998;110:22-31. [Context Link]
92. Bellas RE, Lee JS, Sonenshein GE. Expression of a constitutive NF-kappa B-like activity is essential for proliferation of cultured bovine vascular smooth muscle cells. J Clin Invest 1995;96:2521-7. [Fulltext Link] [Medline Link] [Context Link]
93. Naruszewicz M, Mirkiewicz E, Olszewski AJ, et al. Thiolation of low-density lipoprotein by homocysteine thiolactone causes increased aggregation and altered interaction with cultured macrophages. Nutr Metab Cardiovasc Dis 1994;4:70-77. [Context Link]
94. Jakubowski H. Metabolism of homocysteine thiolactone in human cell cultures: possible mechanism for pathological consequences of elevated homocysteine levels. J Biol Chem 1997;272:1935-42. [Medline Link] [Context Link]
95. McCully KS. Chemical pathology of homocysteine. I. Atherogenesis. Ann Clin Lab Sci 1993;23:477-93. [Medline Link] [Context Link]
96. McCully KS. Chemical pathology of homocysteine. II. Carcinogenesis and homocysteine thiolactone metabolism. Ann Clin Lab Sci 1994;24:27-59. [Medline Link] [Context Link]
97. McCully KS. Chemical pathology of homocysteine. III. Cellular function and aging. Ann Clin Lab Sci 1994;24:134-52. [Medline Link] [Context Link]
98. McCully KS. Homocysteine metabolism in scurvy, growth and arteriosclerosis. Nature 1971;231:391-2. [Context Link]
99. Morel DW, Hessler JR, Chisolm GM. Low density lipoprotein cytotoxicity induced by free radical peroxidation of lipid. J Lipid Res 1983;24:1070-6. [Medline Link] [Context Link]
100. Hughes H, Mathews B, Lenz ML, Guyton JR. Cytotoxicity of oxidized LDL to porcine aortic smooth muscle cells is associated with the oxysterols 7-ketocholesterol and 7-hydroxycholesterol. Arterioscler Thromb 1994;14:1177-85. [Medline Link] [Context Link]
101. Heinecke JW, Kawamura M, Suzuki L, Chait A. Oxidation of low density lipoprotein by thiols: superoxide-dependent and -independent mechanisms. J Lipid Res 1993;34:2051-61. [Medline Link] [Context Link]
102. Parthasarathy S. Oxidation of low-density lipoprotein by thiol compounds leads to its recognition by the acetyl LDL receptor. Biochim Biophys Acta 1987;917:337-40. [Medline Link] [Context Link]
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