bluuebunny/crossref_metadata_2025 huggingface dataset:
Infection and Inflammation Induce LDL Oxidation In Vivo
Authors: Memon Riaz A. , Staprans Ilona , Noor Mustafa , Holleran Walter M. , Uchida Yoshikazu , Moser Arthur H. , Feingold Kenneth R. , Grunfeld Carl
Published: June 2011

Abstract
—Epidemiological studies have shown an increased incidence of coronary artery disease in patients with chronic infections and inflammatory disorders. Because oxidative modification of lipoproteins plays a major role in atherosclerosis, the present study was designed to test the hypothesis that the host response to infection and inflammation induces lipoprotein oxidation in vivo. Lipoprotein oxidation was measured in 3 distinct models of infection and inflammation. Syrian hamsters were injected with bacterial lipopolysaccharide (LPS), zymosan, or turpentine to mimic acute infection, acute systemic inflammation, and acute localized inflammation, respectively. Levels of oxidized fatty acids in serum and lipoprotein fractions were measured by determining levels of conjugated dienes, thiobarbituric acid–reactive substances, and lipid hydroperoxides. Our results demonstrate a significant increase in conjugated dienes and thiobarbituric acid–reactive substances in serum in all 3 models. Moreover, LPS and zymosan produced a 4-fold to 6-fold increase in conjugated diene and lipid hydroperoxide levels in LDL fraction. LPS also produced a 17-fold increase in LDL content of lysophosphatidylcholine that is formed during the oxidative modification of LDL. Finally, LDL isolated from animals treated with LPS was significantly more susceptible to ex vivo oxidation with copper than LDL isolated from saline-treated animals, and a 3-fold decrease occurred in the lag phase of oxidation. These results demonstrate that the host response to infection and inflammation increases oxidized lipids in serum and induces LDL oxidation in vivo. Increased LDL oxidation during infection and inflammation may promote atherogenesis and could be a mechanism for increased incidence of coronary artery disease in patients with chronic infections and inflammatory disorders.
Cardiovascular Effects of Droloxifene, a New Selective Estrogen Receptor Modulator, in Healthy Postmenopausal Women
Authors: Herrington David M. , Pusser Benjamin E. , Riley Ward A. , Thuren Tom Y. , Brosnihan K. Bridget , Brinton Eliot A. , MacLean David B.
Published: June 2011

Abstract
—Selective estrogen receptor modulators, like tamoxifen and related compounds, have mixed estrogen agonistic/antagonistic effects. Tamoxifen may confer significant cardiovascular benefits without the estrogen-associated risks of endometrial and breast cancer. Droloxifene, a structural analogue of tamoxifen, has estrogen agonistic effects on bone and antagonistic effects on endometrial and breast tissue. Its cardiovascular effects in women are unknown. We enrolled 24 healthy postmenopausal women in a randomized, double-blind, 2-period crossover trial comparing the effects of droloxifene (60 mg/d) with conjugated estrogen (0.625 mg/d). Plasma lipids, coagulation and fibrinolytic factors, and brachial flow-mediated vasodilator responses were measured at the beginning and end of each treatment period. Droloxifene and estrogen resulted in 16.6% and 12.0% reductions, respectively, in low density lipoprotein cholesterol (
P
<0.001) and 13.2% and 9.5% reductions, respectively, in lipoprotein(a) (
P
<0.05). In contrast, estrogen, but not droloxifene, increased high density lipoprotein (18.5%,
P
<0.001). Droloxifene also reduced fibrinogen by 17.8% versus a 7.3% reduction with estrogen (
P
=0.004) but produced no estrogen-like changes in plasminogen, plasminogen activator inhibitor-1, or tissue plasminogen activator. Droloxifene and estrogen produced 36.4% and 27.3% increases, respectively, in flow-mediated vasodilation (percent change from baseline,
P
<0.05 for both). Droloxifene has estrogen agonistic properties regarding low density lipoprotein and lipoprotein(a) metabolism, certain coagulation factors, and endothelium-dependent vasodilation but, unlike estrogen, has no effect on high density lipoprotein/triglyceride metabolism and the fibrinolytic cascade. It remains unknown whether droloxifene can confer a true cardiovascular benefit.
Hyperbaric Oxygen Reduces the Progression and Accelerates the Regression of Atherosclerosis in Rabbits
Authors: Kudchodkar Bhalchandra J. , Wilson Judy , Lacko Andras , Dory Ladislav
Published: June 2011

Abstract
—We studied the effect of hyperbaric oxygen (HBO) treatment on the extent of diet-induced accumulation of lipid oxidation products in rabbit plasma and tissues, on plasma paraoxonase activity, and on the extent of progression and regression of atherosclerotic lesions in the rabbit aorta. HBO treatment of cholesterol-fed rabbits dramatically reduces the development of arterial lesions despite having little or no effect on plasma or individual lipoprotein cholesterol concentrations. Compared with no treatment in cholesterol-fed animals, HBO treatment also substantially reduces the accumulation of lipid oxidation products (conjugated dienes, trienes, and thiobarbituric acid–reactive substances) in plasma, in the low density lipoprotein and high density lipoprotein fractions of plasma, in the liver, and in the aortic tissues. In addition, HBO treatment prevents the decrease in plasma paraoxonase activity observed in rabbits fed cholesterol-rich diets. Similarly, in regression studies, HBO treatment has no effect on the rate of plasma (or lipoprotein) cholesterol decline but significantly accelerates aortic lesion regression compared with no treatment. Direct measures of aortic cholesterol content support these morphological observations. On the basis of these results, we conclude that repeated, but relatively short, exposure to HBO induces an antioxidant defense mechanism(s) that is responsible for retarding the development or accelerating the regression of atherosclerotic lesions.
Expression of Allograft Inflammatory Factor-1 Is a Marker of Activated Human Vascular Smooth Muscle Cells and Arterial Injury
Authors: Autieri Michael V. , Carbone Christopher , Mu Anbin
Published: June 2011

Abstract
—The cytokine-induced activation and proliferation of medial vascular smooth muscle cells (VSMCs) leading to intimal hyperplasia is one of the most critical cellular events in the formation of transplant arteriopathy and balloon angioplasty-induced restenosis. Allograft inflammatory factor-1 (AIF-1) is a calcium-binding protein that we have previously shown to be expressed in balloon angioplasty–injured rat carotid arteries. We hypothesized that AIF-1 expression may be associated with the VSMC response to injury. In this study, we examined AIF-1 expression in immunologic and mechanical models of arterial injury. Reverse transcription–polymerase chain reaction and Western analysis demonstrated that AIF-1 is acutely and transiently expressed in aortic medial smooth muscle cells of rat cardiac allografts, with mRNA and protein peaking at 3 to 7 days after transplant and declining by 10 days after transplant. Immunohistochemical analysis identified abundant AIF-1 in the medial VSMCs of these vessels. Immunohistochemical analysis of balloon angioplasty–injured swine coronary arteries also demonstrates an acute AIF-1 expression detectable by 24 hours and continuing up to 14 days after the procedure. AIF-1 in these vessels also localizes to the medial VSMCs and cells of the developing neointima. AIF-1 protein is not expressed in quiescent cultured human VSMCs but is induced in cells challenged with various inflammatory cytokines, primarily by interferon-γ, interleukin-1β, and T-cell–conditioned media. Transfection and overexpression of AIF-1 in human VSMCs result in enhanced growth of these cells. Taken together, these data indicate that AIF-1 expression is associated with vascular trauma and suggest that this protein may play a role in VSMC activation subsequent to arterial injury.
Hyperlipidemia Promotes Thrombosis After Injury to Atherosclerotic Vessels in Apolipoprotein E–Deficient Mice
Authors: Eitzman Daniel T. , Westrick Randal J. , Xu Zuojun , Tyson Julia , Ginsburg David
Published: June 2011

Abstract
—The increased risk of hyperlipidemia on the development of complications of atherosclerosis is well established. Cholesterol-lowering therapies lead to a decrease in the incidence of vascular thrombotic events that is out of proportion to the reduction in plaque size. This suggests that the occurrence of acute thrombosis overlying a disrupted plaque is influenced by changes in lipid levels. The influence of acute hyperlipidemia on the development of thrombosis overlying an atherosclerotic plaque in vivo has not been extensively studied. We used a murine model of vascular injury induced by a photochemical reaction to elicit thrombus formation overlying an atherosclerotic plaque. Fifteen apolipoprotein E–deficient mice were maintained on normal chow until the age of 30 weeks. Five days before the induction of thrombosis, 6 mice were started on a high fat diet, and 9 mice were continued on normal chow. Mice then underwent photochemical injury to the common carotid artery immediately proximal to the carotid bifurcation, where an atherosclerotic plaque is consistently present. Mice maintained on normal chow developed occlusive thrombi, determined by cessation of blood flow, 44±5 minutes (mean±SEM) after photochemical injury, whereas mice fed a high fat chow developed occlusive thrombosis at 27±3 minutes (
P
<0.02). Histological analysis confirmed the presence of acute thrombus formation overlying an atherosclerotic plaque. These studies demonstrate a useful model for assessing the determinants of thrombosis in the setting of atherosclerosis and show that acute elevations in plasma cholesterol facilitate thrombus formation at sites of atherosclerosis after vascular injury.
Plasma Lipoproteins Enhance Tissue Factor–Independent Factor VII Activation
Authors: Kjalke Marianne , Silveira Angela , Hamsten Anders , Hedner Ulla , Ezban Mirella
Published: June 2011

Abstract
—The effect of plasma lipoprotein fractions (large very-low-density lipoprotein, small very-low-density lipoprotein, intermediate-density lipoprotein, and low-density lipoprotein) on initiation of blood coagulation by supporting factor VII activation or by stimulating monocytes to express tissue factor was investigated in vitro. Endotoxin-free preparations of lipoprotein fractions did not induce functional tissue factor in monocytes, whereas all lipoprotein fractions enhanced tissue factor–independent activation of factor VII by factor Xa and by factors Xa/Va. In contrast, no or only slight enhancement of factor IXa–, factor IXa/VIIIa–, factor XIa–, or thrombin-mediated factor VII activation was observed. The effect of small very-low-density lipoprotein was less than that of large very-low-density lipoprotein, and intermediate-density and low-density lipoproteins caused an even lower but still significant increase of factor Xa– and factor Xa/Va–mediated factor VII activation. When the data were normalized for apolipoprotein B-100 content, differences remained between lipoprotein fractions. In contrast, when phospholipid content was used for normalization, differences between lipoprotein fractions in factor Xa– and factor Xa/Va–mediated factor VII activation disappeared, indicating that phospholipids were involved in factor VII activation. This was supported by enhancement of factor Xa–mediated factor VII activation by synthetic phospholipid vesicles containing negatively charged phospholipids.
Social Determinants of von Willebrand Factor
Authors: Kumari Meena , Marmot Michael , Brunner Eric
Published: June 2011

Abstract
—Data from the Whitehall II Study and others have demonstrated a role for the metabolic syndrome and fibrinogen underlying the association between social position and coronary heart disease. In this study, we examined the role of an additional hemostatic factor and marker of endothelial dysfunction, von Willebrand factor (vWF). Four thousand five hundred and forty-eight men and 1837 women were examined in the third phase of the study, which took place between 1991 and 1993. Employment grade was used as a measure of socioeconomic position. An inverse relation between employment grade and vWF was evident (
P
<0.0003). This employment grade gradient was apparent overall, and the relation persisted even when nonsmokers and participants with poor health were removed from the analyses (
P
=0.02). The difference between the highest (unified grades 1 to 6) and lowest (clerical/support) employment grades in vWF concentrations was 8.9 IU/dL (95% CI 6.0, 11.8;
P
<0.001) for men and 6.9 IU/dL (95% CI 4.0, 9.7;
P
=0.06) for women. vWF was associated with a number of biological factors that themselves showed an employment grade gradient, including fibrinogen (
P
<0.001), fasting and postload glucose (
P
<0.05) levels, and fasting and postload insulin (
P
<0.01) levels. Associations with smoking and alcohol intake were apparent. Smoking showed a threshold effect, such that only men who smoked >21 cigarettes per day produced a significantly increased vWF level (
P
<0.05) compared with lighter smokers. The health-related behaviors explained 25% of the grade gradient in men and 28% in women, while the biological factors accounted for 32% in men and 22% in women. We conclude that there is a grade gradient in vWF that was not fully explained by health-related behaviors and risk factors for coronary heart disease. These data are consistent with the hypothesis that endothelial dysfunction is part of the explanation for social inequalities in cardiovascular disease.
Pathogenicity of Thermolabile Methylenetetrahydrofolate Reductase for Vascular Dementia
Authors: Yoo Jun-Hyun , Choi Gyu-Dong , Kang Soo-Sang
Published: June 2011

Abstract
—Although the major biochemical abnormality due to methylenetetrahydrofolate reductase (MTHFR) deficiency is hyperhomocyst(e)inemia, its pathogenicity appears to involve more than homocysteine toxicity. In patients with severe MTHFR deficiency, a metabolite(s) other than hyperhomocyst(e)inemia also appears to be associated with its clinical manifestation in cerebrovascular disease. To elucidate the specific role of the TT genotype of MTHFR in the development of cerebral infarction with and without cognitive impairment, we determined the prevalence of hyperhomocyst(e)inemia and the C677T genotypes of MTHFR in 143 patients with vascular dementia, 122 patients with cerebral infarction, and 217 healthy subjects matched for age and sex. Prevalence of hyperhomocyst(e)inemia [homocyst(e)ine ≥15 μmol/L] was higher in cerebrovascular patients with or without dementia than in normal control subjects (42.6%, 20.5%, and 10.1%, respectively;
P
=0.001). In contrast, a higher frequency of MTHFR TT genotype was found only in demented patients compared with nondemented patients and healthy controls (25.2%, 9.8%, and 12.0%, respectively;
P
=0.01). When the study subjects were divided into normohomocyst(e)inemic and hyperhomocyst(e)inemic groups, the TT genotype was significantly associated with the risk for vascular dementia in the hyperhomocyst(e)inemic group (odds ratio 4.13, 95% CI 2.18 to 7.85;
P
=0.03) but not in the normohomocyst(e)inemic group. Demented patients with multiple infarcts had a higher frequency of TT genotype (odds ratio 3.13, 95% CI 2.23 to 4.39;
P
=0.0007), whereas those with a single infarct did not (odds ratio 2.03,
P
=0.15). In contrast, there was no significant association of the TT genotype with multiple infarcts in hyperhomocyst(e)inemic stroke patients. Taken together, these findings indicate a possible role of MTHFR TT genotype combined with hyperhomocyst(e)inemia in the pathogenesis of vascular dementia. Similar to the relationship between homocystinuria due to severe MTHFR deficiency and severe cystathionine β-synthase deficiency, the TT genotype of MTHFR in hyperhomocyst(e)inemic subjects is differentiated from the cases of the TT genotype without hyperhomocyst(e)inemia or hyperhomocyst(e)inemia without the TT genotype in the development of cerebrovascular disease.
Progression of Aortic Calcification Is Associated With Metacarpal Bone Loss During Menopause
Authors: Hak A. Elisabeth , Pols Huibert A. P. , van Hemert Albert M. , Hofman Albert , Witteman Jacqueline C. M.
Published: June 2011

Abstract
—Atherosclerosis and osteoporosis are major causes of morbidity and mortality in postmenopausal women and have been suggested to be associated. No study has examined whether progression of atherosclerotic calcification is associated with bone loss. In the present study, we examined progression of aortic calcification, diagnosed by radiographic detection of calcified deposits in the abdominal aorta, in relation to metacarpal bone loss, as assessed by metacarpal radiogrammetry, during menopause. Initially premenopausal women (n=236), aged 45 to 57 years at baseline, were followed for 9 years. We additionally assessed the cross-sectional association between the extent of aortic calcification and metacarpal bone mass and density in 720 postmenopausal women. Twenty-five percent of women going through menopause showed progression of aortic calcification. The average loss of metacarpal bone mass among women with progression of aortic calcification was 3.2 mm
2
, and their loss of metacarpal bone density was 7.2 mm
2
%, whereas in women without progression of aortic calcification, these losses were 2.0 mm
2
and 5.6 mm
2
%, respectively, adjusted for age and years of follow-up (
P
<0.05). Additional adjustment for age at menopause, body mass index, blood pressure, smoking, diabetes mellitus, and use of hormone replacement therapy, thiazide, and loop diuretics did not influence these results. In postmenopausal women, a graded inverse cross-sectional association between the extent of aortic calcification and metacarpal bone mass and density was found. In conclusion, our results indicate that progression of atherosclerotic calcification is associated with increased bone loss in women during menopause.
Race, Visceral Adipose Tissue, Plasma Lipids, and Lipoprotein Lipase Activity in Men and Women
Authors: Després Jean-Pierre , Couillard Charles , Gagnon Jacques , Bergeron Jean , Leon Arthur S. , Rao D. C. , Skinner James S. , Wilmore Jack H. , Bouchard Claude
Published: June 2011

Abstract
—Abdominal obesity is associated with numerous metabolic alterations, such as hypertriglyceridemia and low levels of high density lipoprotein (HDL) cholesterol. However, compared with abdominally obese white individuals, abdominally obese black individuals have been characterized by higher plasma HDL cholesterol levels, suggesting that the impact of abdominal fat accumulation on the lipoprotein-lipid profile may differ among ethnic groups. Therefore, we have compared the associations between body fatness, visceral adipose tissue (AT) accumulation, and metabolic risk variables in a sample of 247 white men and 240 white women versus a sample of 93 black men and 143 black women. Although no difference in mean total body fatness was found between the 2 race groups, white men had higher levels of visceral AT than did black men (
P
<0.001). Despite the fact that black women had a greater body fat content than did white women, black women had levels of visceral AT that were similar to those of white women, suggesting a lower susceptibility to visceral obesity in black women. This lower accumulation of visceral AT in blacks was accompanied by significantly reduced apolipoprotein B concentrations and ratios of total cholesterol to HDL cholesterol as well as higher plasma HDL cholesterol levels (
P
<0.05) compared with those values in whites. Irrespective of sex, higher postheparin plasma hepatic lipase (HL) and lower lipoprotein lipase (LPL) activities were found in whites, resulting in an HL/LPL ratio that was twice as high in whites as in blacks (
P
<0.005). Although differences in lipoprotein-lipid levels were noted between whites and blacks, results from multiple regression analyses revealed that after control for morphometric and metabolic variables of the study (body fat mass, visceral AT, LPL, HL, and age), ethnicity had, per se, only a minor contribution to the variance in plasma lipoprotein levels. Thus, our results suggest that the higher plasma HDL cholesterol levels and the generally more cardioprotective plasma lipoprotein profile found in abdominally obese black versus white individuals are explained, at least to a certain extent, by a lower visceral AT deposition and a higher plasma LPL activity in black individuals.
Short-Term Feeding of Atherogenic Diet to Mice Results in Reduction of HDL and Paraoxonase That May Be Mediated by an Immune Mechanism
Authors: Hedrick Catherine C. , Hassan Kholood , Hough Greg P. , Yoo JiHyung , Simzar Soheil , Quinto Cindy R. , Kim Sul-Min , Dooley Alek , Langi Sesilia , Hama Susan Y. , Navab Mohamad , Witztum Joseph L. , Fogelman Alan M.
Published: June 2011

Abstract
—Short-term feeding (up to 7 days) of an atherogenic diet to C57BL/6 low density lipoprotein receptor–deficient mice did not result in decreased hepatic paraoxonase (PON) mRNA but caused a dramatic decrease in plasma PON activity and mass. The decreased activity and mass were temporally related to an increase in plasma and high density lipoprotein (HDL) lipid hydroperoxides and to a decrease in HDL cholesterol and native apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II). As the native apoA-I protein disappeared from the circulation, higher molecular weight forms of apoA-I appeared, some of which contained epitopes recognized by an antibody (EO6) that recognizes oxidized phospholipids. After mice consumed an atherogenic diet for 1 or 3 days, switching the mice to a low fat chow diet for 3 days resulted in a return to baseline levels of lipid hydroperoxides but only a small return toward baseline for HDL cholesterol, with no significant increase in apoA-I mass or PON activity and mass. After mice consumed an atherogenic diet for 3 days, switching to the chow diet for 3 days did not significantly alter the high molecular weight forms of apoA-I or the signal generated by EO6. In marked contrast, after mice consumed an atherogenic diet for 7 days, switching to the chow diet for 3 days resulted in a dramatic increase in native apoA-I to baseline levels, with virtual disappearance of the high molecular weight forms of apoA-I, including the form recognized by EO6. After mice consumed an atherogenic diet for 7 days, switching to the chow diet for 3 days also resulted in significant increases in HDL cholesterol and PON mass and activity, although baseline levels were not reached. IgG and IgM antibodies were found to be associated with apoA-I in control animals, were minimally decreased after the 3-day atherogenic diet, were dramatically decreased after the 7-day atherogenic diet, and returned to near or above baseline levels after a return to the chow diet for 3 days. We conclude that the atherogenic diet rapidly induces lipid hydroperoxide formation and apoA-I oxidation with the formation of high molecular weight forms of apoA-I. Concomitant with these changes in apoA-I levels, HDL cholesterol and PON activity and mass declined without changes in mRNA levels for apoA-I or PON, suggesting increased clearance of these altered HDL particles. We further conclude that between the third and seventh day of the atherogenic diet, an as-yet-unidentified mechanism for clearing the high molecular weight forms of apoA-I is induced and that this mechanism may be related to the clearance of immune complexes.
Chronic
N
G
-Nitro-
l
-Arginine Methyl Ester Treatment Does Not Prevent Flow-Induced Remodeling in Mesenteric Feed Arteries and Arcading Arterioles
Authors: Ceiler Debbie L. , De Mey Jo G. R.
Published: June 2011

Abstract
—Although endothelium-derived NO is an important mediator in acute flow-induced changes in arterial tone, the role of NO in chronic flow-induced changes in the resistance artery and arteriolar structure remains largely unresolved. We investigated the effects of chronic inhibition of NO synthase on arterial and arteriolar remodeling in a rat mesenteric model in which flow changes were induced. Alternating first-order mesenteric arteries were ligated to shunt blood flow through the intermittent patent arteries. Animals received no treatment (NT) or a continuous infusion of
N
G
-nitro-
l
-arginine methyl ester (L-NAME, 25 mg/kg SC per day). After 2 weeks, local in vivo blood flow and in vitro arterial pressure-diameter relationships were assessed, as were the in situ diameters of arcading arterioles. Medial cross-sectional areas (CSAs) were measured histologically. In both groups of animals, blood flow was significantly increased in patent arteries and decreased in ligated arteries compared with control vessels. Nonetheless, in L-NAME–treated rats, patent artery flow was increased to a lesser extent, although control flow was not significantly reduced (0.18±0.05 versus 0.26±0.05 mL/min). In NT rats, the diameter of patent arteries was significantly larger and the diameter of ligated arteries was significantly smaller than that of control arteries. CSAs displayed the same pattern of change (11.9±0.6×10
3
, 6.1±0.7×10
3
, and 8.2±1.0×10
3
μm
2
for patent, ligated, and control arteries, respectively). Arterioles in the NT collateral pathway (218±15 μm) had diameters similar to control arteriole diameters (201±15 μm) but had a significantly larger CSA (6.2±0.6×10
3
versus 4.2±0.4×10
3
μm
2
). In L-NAME–treated rats, the flow-induced changes of the diameter and CSA in patent arteries, ligated arteries, and arcading arterioles mimicked those in NT rats. Nonetheless, control feed arteries (430±21 versus 497±16 μm) and arcading arterioles (156±21 μm) were significantly narrower after L-NAME treatment. Thus, chronic blockade of NO oxide synthase (1) tended to reduce arterial blood flow and resulted in inward remodeling of mesenteric arteries and arterioles and (2) did not prevent arterial and arteriolar remodeling in response to imposed changes in blood flow. Endothelium-derived mediators other than NO can play a major role in flow-induced arterial remodeling.
Cytokines Induce Upregulation of Vascular P2Y
2
Receptors and Increased Mitogenic Responses to UTP and ATP
Authors: Hou Mingyan , Möller Sebastian , Edvinsson Lars , Erlinge David
Published: June 2011

Abstract
—P2Y
2
receptors, which mediate contractile and mitogenic effects of extracellular nucleotides in vascular smooth muscle cells (VSMCs), are upregulated in the synthetic phenotype of VSMCs and in the neointima after balloon angioplasty, suggesting a role in the development of atherosclerosis. Because released cytokines in atherosclerotic lesions mediate multiple effects on gene transcription in VSMCs, we speculated that cytokines could be involved in the regulation of P2Y
2
receptor expression. Using a competitive reverse transcription–polymerase chain reaction, we detected that interleukin (IL)-1β induced a time- and dose-dependent upregulation of P2Y
2
receptor mRNA, which was dramatically enhanced when combined with interferon-γ or tumor necrosis factor-α. Lipopolysaccharide also significantly increased the expression of P2Y
2
receptor mRNA. The upregulation of P2Y
2
receptor mRNA was paralleled at the functional level because IL-1β significantly increased the UTP-stimulated DNA synthesis and the release of intracellular Ca
2+
. Actinomycin D completely blocked the upregulation of P2Y
2
receptor mRNA expression by IL-1β, indicating de novo mRNA synthesis. There was no cAMP accumulation in the cells stimulated with IL-1β. The cyclooxygenase inhibitor indomethacin and the protein kinase C inhibitor RO-31-8220 inhibited IL-1β–induced upregulation of P2Y
2
receptor mRNA expression, whereas rapamycin and PD098059 had no effects. Furthermore, neither P38 mitogen-activated protein kinase inhibitor SB20358 alone nor its combination with PD098059 blocked the effect of IL-1β on the expression of P2Y
2
receptor mRNA. Our results demonstrate that inflammatory mediators upregulate vascular P2Y
2
receptors at the transcriptional and at the functional level through protein kinase C and cyclooxygenase but not cAMP, extracellular signal–regulated kinases 1 and 2, or P38-dependent pathways. This may result in increased growth-stimulatory or contractile effects of extracellular UTP and ATP, which may be of importance in the development of vascular disease.
Vitamin E Supplementation of Human Macrophages Prevents Neither Foam Cell Formation Nor Increased Susceptibility of Foam Cells to Lysis by Oxidized LDL
Authors: Asmis Reto , Jelk Jennifer
Published: June 2011

Abstract
—Several studies in macrophage cell lines, rodent macrophages, and animal models of atherosclerosis suggest that vitamin E may prevent the formation of foam cells. We tested this hypothesis in a recently developed, fully autologous in vitro model of human foam cell formation. During maturation, macrophages continuously increased their α-tocopherol/total cholesterol ratio, demonstrating that these cells accumulate α-tocopherol at an even higher rate than cholesterol. In the presence of unsupplemented serum, we observed no correlation between serum vitamin E levels and the increase in the cellular α-tocopherol/total cholesterol ratio. In contrast, under supplemented conditions, a 3.1-fold increase in the mean serum α-tocopherol/total cholesterol ratio resulted in a corresponding mean 3.5-fold increase in the cellular α-tocopherol/total cholesterol ratio. Vitamin E loading had no effect on the lipid composition of macrophages and did not affect their growth. Foam cell formation was stimulated in mature unsupplemented and vitamin E–loaded macrophages for 1 week with 50 μg autologous aggregated low density lipoprotein (LDL) in the presence of unsupplemented and vitamin E–loaded serum, respectively. We observed no effect of vitamin E supplementation on the formation of foam cells. However, foam cell formation resulted in a 36% and 44% reduction in the cellular α-tocopherol/total cholesterol ratio in unsupplemented and vitamin E–supplemented foam cells, respectively. The loss of vitamin E was accelerated with increasing concentrations of aggregated LDL and was accompanied by an increase in the susceptibility of these foam cells to succumb to the cell lytic effects of oxidized LDL (OxLDL). However, vitamin E supplementation did not protect macrophages or foam cells from OxLDL-mediated cell lysis, suggesting that vitamin E loss in foam cells is not the cause of their increased susceptibility to cell lysis. Our results suggest that the beneficial effects of vitamin E on cardiovascular disease observed in humans are due neither to a reduction in the propensity of macrophages to form foam cells nor to an increased resistance of these cells to cytolytic OxLDL.
Arginine Intake and Risk of Coronary Heart Disease Mortality in Elderly Men
Authors: Oomen Claudia M. , van Erk Marjan J. , Feskens Edith J. M. , Kok Frans J. , Kromhout Daan
Published: June 2011

Abstract
—From experimental studies, the hypothesis is derived that the amino acid arginine, the precursor of NO, could restore the impaired endothelial function and increased platelet activation observed in atherosclerosis. We investigated whether dietary intake of arginine is associated with reduced coronary heart disease risk in elderly persons. The study population consisted of 806 men aged 64 to 84 years at baseline who participated in the Zutphen Elderly Study, a population-based cohort followed up for 10 years. Information about habitual food consumption was collected by use of the cross-check dietary history method. Ninety (11.2%) of the 806 men died from coronary heart disease. Mean±SD baseline arginine intake was 4.35±1.07 g/d. Meat was the main source of arginine intake (37.1%), followed by bread (13.1%) and milk and milk products (12.1%). Arginine intake was not associated with coronary heart disease mortality. After adjustment for age, the relative risk (RR) for the medium tertile of arginine intake was 0.72 (95% CI 0.44 to 1.18), and the RR for the highest tertile was 0.71 (95% CI 0.43 to 1.19,
P
for trend=0.19) compared with the lowest tertile of arginine intake. After additional adjustment for history of coronary heart disease and diabetes mellitus, energy intake, body mass index, smoking habit, physical activity, and other relevant dietary and biological risk factors, the RR was 1.86 (95% CI 1.06 to 3.27) for the medium intake and 1.56 (95% CI 0.83 to 2.93) for the highest intake (
P
for trend=0.17). These results do not support the hypothesis that dietary arginine intake lowers the risk of coronary heart disease mortality.
Concentrations of Electrophoretic and Size Subclasses of Apolipoprotein A-I–Containing Particles in Human Peripheral Lymph
Authors: Nanjee M. N. , Cooke C. J. , Olszewski W. L. , Miller N. E.
Published: June 2011

Abstract
—When cultured cells are exposed to plasma, the initial acceptors of unesterified cholesterol are small lipid-poor apolipoprotein A-I (apoA-I)–containing high density lipoproteins (HDLs) with pre-β electrophoretic mobility. These are converted by lecithin:cholesterol acyltransferase into larger spheroidal cholesteryl ester–rich HDLs with α mobility. To study the determinants of the concentration of small pre-β HDLs in tissue fluids, we collected prenodal peripheral lymph from 34 fasted normal men. By crossed immunoelectrophoresis, the concentration of pre-β HDLs in lymph averaged 20% of that in plasma. On multiple regression analysis, pre-β apoA-I concentration in lymph was directly related to pre-β apoA-I concentration in plasma and independently to α apoA-I concentration in lymph. Similar results were obtained when the same apoA-I–containing particles were quantified by size exclusion chromatography. Lymph pre-β apoA-I concentration was low in a subject with familial lecithin:cholesterol acyltransferase deficiency, despite a normal plasma pre-β apoA-I concentration, but was normal in a subject with familial lipoprotein lipase deficiency. These results suggest that the concentration of small pre-β HDLs in human tissue fluids is determined only in part by the transfer of pre-β HDLs across capillary endothelium from plasma. Local production, by remodeling of spheroidal α HDLs in tissue fluids, may be equally important. Lipolysis of triglyceride-rich lipoproteins by lipoprotein lipase appears to have little effect.
Thrombin-Activatable Fibrinolysis Inhibitor Antigen Levels and Cardiovascular Risk Factors
Authors: Juhan-Vague I. , Renucci J. F. , Grimaux M. , Morange P. E. , Gouvernet J. , Gourmelin Y. , Alessi M. C.
Published: June 2011

Abstract
—Thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently described fibrinolysis inhibitor that circulates in plasma as a procarboxypeptidase and is converted into an active form during coagulation. The physiological relevance of TAFI is not known, but it might be involved in pathways regulating fibrin deposition. Our aim was to determine the interindividual variability of plasma TAFI antigen values and their associations with conventional cardiovascular risk factors. Six hundred twenty-six consecutive patients (277 men) attending a metabolic ward for primary prevention were studied. TAFI antigen presented a large range of values, with a 2- to 3-fold increase between the 10th and 90th percentiles. No difference was observed between the 2 sexes. A significant correlation was observed between age and TAFI levels in women only. After adjustment for age, TAFI antigen was positively correlated in men for the waist-to-hip circumference ratio and blood pressure, whereas no significant correlation was observed in women. Stepwise multiple linear regression analysis indicated a low contribution of the parameters studied to the variability of TAFI antigen levels; the waist-to-hip circumference ratio accounted for only 2% in men, and age accounted for only 3% in women. Results were compared with those of fibrinogen and plasminogen activator inhibitor-1; cardiovascular risk factors in men and women accounted for 16% and 9.5%, respectively, of the fibrinogen variance and 36% and 32%, respectively, of the plasminogen activator inhibitor-1 variance. These observations did not attribute an important role to lifestyle characteristics in the control of TAFI antigen concentration in plasma. Because of the large interindividual variability of TAFI levels in plasma, genetic control may be involved.
LDL Immunization Induces T-Cell–Dependent Antibody Formation and Protection Against Atherosclerosis
Authors: Zhou Xinghua , Caligiuri Giuseppina , Hamsten Anders , Lefvert Ann Kari , Hansson Göran K.
Published: June 2011

Abstract
—Atherosclerosis is an inflammatory disease, and the involvement of immune mechanisms in disease progression is increasingly recognized. Immunization with oxidized low density lipoprotein (LDL) decreases atherosclerosis in several animal models. To explore humoral and cellular immune reactions involved in this protection, we immunized apolipoprotein E knockout mice with either homologous plaque homogenates or homologous malondialdehyde (MDA)-LDL. Immunization with both these antigen preparations reduced lesion development. The plaques contained immunogen(s) sharing epitopes on MDA-LDL, MDA–very low density lipoprotein, and oxidized cardiolipin. This shows that a T-cell–dependent antibody response was associated with protection against atherosclerosis. The protection was associated with specific T-cell–dependent elevation of IgG antibodies against MDA-LDL and oxidized phospholipids, and the increased titers of IgG antibodies were correlated with decreased lesion formation and lower serum cholesterol levels.
Simvastatin Preserves Coronary Endothelial Function in Hypercholesterolemia in the Absence of Lipid Lowering
Authors: Wilson Stephanie H. , Simari Robert D. , Best Patricia J. M. , Peterson Tim E. , Lerman Lilach O. , Aviram Michael , Nath Karl A. , Holmes David R. , Lerman Amir
Published: June 2011

Abstract
—Recent evidence suggests that some benefit from the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may occur independent of lipid lowering. We aimed to determine the effect of simvastatin on coronary endothelial function, endothelial NO synthase (eNOS) expression, and oxidative stress in experimental hypercholesterolemia (HC) in the absence of cholesterol lowering. Pigs were randomized to 3 experimental groups: normal diet (N group), high cholesterol diet (HC group), and HC diet with simvastatin (HC+S group) for 12 weeks. Low density lipoprotein cholesterol was similarly increased in the HC and HC+S groups compared with the N group. In vitro analysis of coronary large- and small-vessel endothelium-dependent vasorelaxation was performed. The mean vasorelaxation of epicardial vessels to bradykinin was significantly attenuated in the HC group compared with the N group (32.3±1.2% versus 42.9±1.6%, respectively;
P
<0.0001). This attenuation was significantly reversed in the HC+S group (38.7±1.5%,
P
<0.005 versus HC group). The maximal vasorelaxation to substance P was significantly attenuated in the HC group compared with the N group (50.5±11.9% versus 79.3±5.3%, respectively;
P
<0.05). This attenuated response was normalized in the HC+S group (74.9±4.1%,
P
<0.05 versus HC group). The maximal arteriolar vasorelaxation to bradykinin was also significantly attenuated in the HC group compared with the N group (71.9±4.9% versus 96.8±1.34%, respectively;
P
<0.005). This was reversed in the HC+S group (98.4±0.6%,
P
<0.0001 versus HC group). Western blotting of coronary tissue homogenates for eNOS demonstrated a decrease in protein levels in the HC group compared with the N group, with normalization in the HC+S group. Elevation of plasma F
2
-isoprostanes and thiobarbituric acid–reactive substances, markers of oxidative stress, occurred in the HC compared with the N group. These changes were reversed in the HC+S group. In summary, simvastatin preserves endothelial function in coronary epicardial vessels and arterioles in experimental HC (in the absence of cholesterol lowering) in association with an increase in coronary eNOS levels and a decrease in oxidative stress. These alterations may play a role in the reduction in cardiac events after treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.
Biglycan, a Vascular Proteoglycan, Binds Differently to HDL
2
and HDL
3
Authors: Olin Katherine L. , Potter-Perigo Susan , Barrett P. Hugh R. , Wight Thomas N. , Chait Alan
Published: June 2011

Abstract
—Lipoprotein retention by vascular extracellular matrix proteoglycans is important in atherogenesis. Proteoglycans bind apolipoprotein (apo)B- and apoE-containing lipoproteins. However, the colocalization of apoA-I and apoE with biglycan in atherosclerotic lesions suggests that vascular proteoglycans also may trap high density lipoproteins (HDLs). Because the major HDL subclasses may be atheroprotective to different degrees, we investigated the role of apoE in mediating HDL
2
and HDL
3
binding to the extracellular vascular proteoglycan, biglycan. ApoE-free HDL
2
and HDL
3
did not bind to purified [
35
S]SO
4
-biglycan, whereas apoE-containing HDL
2
and HDL
3
(HDL+E) did. The extent of binding correlated positively with the apoE content for both HDL
2
and HDL
3
, although HDL
2
+E had a 3.5-fold higher affinity than did HDL
3
+E. ApoE on HDL
3
was cleaved into 22- and 12-kDa fragments, whereas apoE on HDL
2
remained intact. These results suggest that the cleaved apoE on HDL
3
results in diminished biglycan binding of HDL
3
+E relative to HDL
2
+E. Reducing positive charges on lysine and arginine residues on HDL+E eliminated biglycan binding, suggesting an ionic interaction. Thus, apoE is an important determinant of HDL binding to extracellular vascular proteoglycans and may play a role in HDL retention in the artery wall.
Sustained Anxiety and 4-Year Progression of Carotid Atherosclerosis
Authors: Paterniti Sabrina , Zureik Mahmoud , Ducimetière Pierre , Touboul Pierre-Jean , Fève Jean-Marc , Alpérovitch Annick
Published: June 2011

Abstract
—Several studies have shown that anxiety disorders are associated with a higher risk of coronary artery disease. However, the relationship between anxiety disorders and atherosclerosis has been studied to a lesser extent. The goal of this study was to examine whether high and stable trait anxiety was associated with the progression of atherosclerosis. The study group consisted of 726 subjects (297 men and 429 women), aged 59 to 71 years, recruited from the electoral rolls of the city of Nantes. The subjects had no history of coronary artery disease at baseline evaluation and or at the 2-year follow-up. Two follow-up examinations were conducted 2 and 4 years after the baseline evaluation. Trait anxiety was evaluated by means of the French translation of the Spielberger Inventory (a 20-item trait inventory, form X-2). The “sustained anxiety” group consisted of men and women with the highest Spielberger Inventory scores at baseline and at the 2-year follow-up examination. Each ultrasound examination included measurement of intima-media thickness and the sites of plaque in the extracranial carotid arteries. Men with sustained anxiety showed a higher 4-year increase of common carotid intima-media thickness than did men without sustained anxiety (adjusted means 0.08 versus 0.04 mm, respectively;
P
=0.05) and a higher risk of 4-year plaque occurrence (adjusted OR 3.5, 95% CI 1.4 to 8.5). Among women, sustained anxiety was associated with a higher 4-year increase of common carotid intima-media thickness (0.07 versus 0.04 for women with versus women without sustained anxiety, respectively;
P
=0.07). These results suggest that chronically high levels of anxiety may contribute to accelerating the evolution of carotid atherosclerosis.
Disaggregation of In Vitro Preformed Platelet-Rich Clots by Abciximab Increases Fibrin Exposure and Promotes Fibrinolysis
Authors: Collet J. P. , Montalescot G. , Lesty C. , Soria J. , Mishal Z. , Thomas D. , Soria C.
Published: June 2011

Abstract
—The glycoprotein IIb/IIIa receptor inhibitor abciximab has been shown to facilitate the rate and the extent of pharmacological thrombolysis with recombinant tissue plasminogen activator (rtPA) in patients with acute myocardial infarction. However, the underlying mechanisms remain not fully determined. We sought to demonstrate that this facilitating effect of abciximab could be related to its potential to modify the clot architecture and the clot physical properties. Compared with fibrin-rich clots, platelets dramatically modified the in vitro properties of the fibrin network, leading to a significant increase of the permeability (
K
s
) and the viscoelasticity (G′) indexes but also leading to the appearance of platelet aggregates (surface area [S.ag]). These modifications resulted in a 2.6-fold decrease of the fibrinolysis rate when rtPA (1 nmol/L) was added before the initiation of clotting. Adding aspirin (100 μg/mL) or abciximab (0.068 μmol/L) before the clotting of platelet-rich clots (PRCs) lowered
K
s
by 50% and 70%, respectively (
P
<0.01), G′ by 41% and 66%, respectively (
P
<0.01), and S.ag by 32% and 61%, respectively (
P
<0.01). As a consequence, the lysis speed was increased by 21% with aspirin (
P
<0.01) and 45% with abciximab (
P
<0.01). However, unlike aspirin, permeation of preformed PRCs with abciximab (0.068 μmol/L) decreased G′ (37%,
P
<0.01),
K
s
(35%,
P
<0.001) and S.ag (25%,
P
=NS) and resulted in a 27% (
P
<0.01) increase of the lysis speed when abciximab and rtPA (0.2 μmol/L) were simultaneously permeated. This effect was found to be time dependent and was observed only with early permeation, starting within the first 10 minutes of clotting. These changes in the physical properties of the PRC architecture suggest that fibrin is removed from the platelet-fibrin aggregates and reexposed into the surrounding fibrin network, increasing rtPA access to fibrin and therefore the fibrinolysis rate. The superiority of abciximab over aspirin in accelerating fibrinolysis of forming and preformed PRCs is related to its ability to modulate the interactions of fibrinogen and fibrin with platelets. These findings provide new mechanistic information on reperfusion therapy.
Comparative Antiplatelet Efficacy of a Novel, Nonpeptide GPIIb/IIIa Antagonist (XV454) and Abciximab (c7E3) in Flow Models of Thrombosis
Authors: Abulencia James P. , Tien Niven , McCarty Owen J. T. , Plymire Daniel , Mousa Shaker A. , Konstantopoulos Konstantinos
Published: June 2011

Abstract
—Glycoprotein (GP) IIb/IIIa is pivotal in homotypic platelet aggregation and may also be involved in the heterotypic adhesion of leukocytes and tumor cells to platelets. This study was primarily undertaken to compare the antiplatelet efficacy of a novel, nonpeptide GPIIb/IIIa antagonist, XV454, to that of abciximab in 2 flow models of platelet thrombus formation: (1) direct shear-induced platelet aggregation imposed by a cone-and-plate rheometer and (2) platelet adhesion onto von Willebrand factor (vWF)/collagen I followed by aggregation in a perfusion system. XV454 inhibited platelet aggregation in a concentration-dependent manner in both experimental models. Maximal inhibition of aggregation was achieved by XV454 at ≈70% receptor occupancy, which is lower than the ≥85% previously reported for abciximab. At similar levels of receptor blockade (≈45%), XV454 appeared to be relatively more effective than abciximab in suppressing platelet aggregation. Neither XV454 nor abciximab inhibited platelet adhesion to collagen. Pretreatment of surface-adherent platelets with either XV454 or abciximab inhibited the attachment of monocytic THP-1 cells under flow. In contrast, the rapidly reversible GPIIb/IIIa inhibitor orbofiban failed to suppress these heterotypic interactions. These findings demonstrate that XV454 is a potent GPIIb/IIIa antagonist with a long receptor-bound lifetime like abciximab and may be beneficial for the treatment/prevention of thrombotic complications.