bluuebunny/crossref_metadata_2025 huggingface dataset:
LDL Subclass Patterns and Lipoprotein Response to a Low-Fat, High-Carbohydrate Diet in Women
Authors: Dreon Darlene M. , Fernstrom Harriett A. , Williams Paul T. , Krauss Ronald M.
Published: June 2011

AbstractA predominance of small, dense LDL particles (subclass pattern B) characterizes a metabolic trait that is associated with higher levels of triglyceride-rich lipoproteins and lower levels of HDL compared with those of individuals with predominantly larger LDL (pattern A). This trait appears to be under the influence of one or more genes, with maximal expression in adult males and reduced expression in premenopausal females. In a previous study, men with LDL subclass pattern B had significantly greater reductions in LDL cholesterol (LDL-C) and apolipoprotein B than men with pattern A. We hypothesized that despite the low prevalence of pattern B in premenopausal women, genetic predisposition to this trait could affect dietary responsiveness. Specifically, we predicted that LDL-C reduction on a low-fat, high-carbohydrate diet would be greatest in daughters of two pattern B parents, intermediate in daughters with one pattern B parent, and least in daughters with no pattern B parents. When 72 premenopausal women were placed on a 20% fat diet for 8 weeks, the changes in LDL-C (mmol/L) compared with levels on basal diets were significantly related to the number of pattern B parents (two B parents: −0.92±0.61, one B parent: −0.23±0.10, no B parents: −0.05±0.06) and could not be explained by diet adherence or baseline characteristics including initial lipoprotein profile or body mass index. The number of pattern B parents was also related to reductions in plasma mass concentrations of IDL, total LDL, and large LDL and to increases in plasma triglycerides. There was a significant inverse correlation between changes in triglyceride and LDL-C induced by the low-fat, high-carbohydrate diet. Thus, genetic and metabolic factors underlying LDL subclass pattern B may result in enhanced LDL and triglyceride responsiveness to substitution of dietary carbohydrate for fat in premenopausal women.
Defects of Insulin Action on Fatty Acid and Carbohydrate Metabolism in Familial Combined Hyperlipidemia
Authors: Aitman Timothy J. , Godsland Ian F. , Farren Bernadette , Crook David , Wong H. John , Scott James
Published: June 2011

Abstract
Familial combined hyperlipidemia (FCHL) is a common cause of premature myocardial infarction, but its metabolic basis is unknown. Insulin resistance has been suggested in some patients by the presence of fasting hyperinsulinemia. We studied insulin action on carbohydrate and fatty acid metabolism in FCHL patients and healthy control subjects by a two-step euglycemic, hyperinsulinemic clamp. During low-dose insulin infusion, steady-state nonesterified fatty acids (NEFAs) were higher in patients than in control subjects (0.36 mmol/L [95% confidence limits, 0.19, 0.53] versus 0.19 mmol/L [0.10, 0.28];
P
=.05). The ratio of steady-state to basal NEFAs was increased by 88% in patients compared with control subjects (
P
=.005). During high-dose insulin infusion, insulin sensitivity for peripheral glucose disposal was reduced by 60% in FCHL patients compared with control subjects (
P
=.03). Hepatic glucose production at baseline and during the clamp was similar in the two groups. In multiple regression analysis, increased upper-body fat in the patient group accounted for the impairment of insulin-mediated glucose disposal but did not influence the defect in insulin-mediated NEFA suppression in the FCHL patients. This defect in fatty acid metabolism may be a primary defect in FCHL that contributes to abnormalities in the secretion and composition of lipoproteins in this disorder. Direct study of this defect may facilitate genetic analysis of this disorder.
Gene Polymorphisms Predicting High Plasma Levels of Coagulation and Fibrinolysis Proteins
Authors: Mannucci P.M. , Mari D. , Merati G. , Peyvandi F. , Tagliabue L. , Sacchi E. , Taioli E. , Sansoni P. , Bertolini S. , Franceschi C.
Published: June 2011

Abstract
Gene polymorphisms associated with the plasma levels of fibrinogen, factor VII, and plasminogen activator inhibitor 1 (PAI-1)—hemostasis proteins that help to predict the risk of atherothrombotic disease—were compared in 124 healthy individuals ≥100 years old and 130 young, healthy individuals to identify genetic influences on extreme longevity. We investigated the restriction fragment length polymorphism G/A
−455
located in the promoter of the β-fibrinogen gene, the guanine insertion/deletion polymorphism 4G/5G in the promoter of the PAI-1 gene, and the R353Q substitution polymorphism in exon 8 of the factor VII gene. Alleles and genotypes associated with elevated plasma levels of fibrinogen and factor VII were found with similar frequencies in centenarians and in the comparison group. However, in centenarians there was a significantly higher frequency of the 4G allele and of the homozygous 4G4G genotype associated with high PAI-1 levels. Since high PAI-1 is considered a predictor of recurrent myocardial infarction in young men, it is intriguing that the corresponding genetic marker is more frequent in centenarians who have escaped major age-related atherothrombotic disease and reached the extreme limits of human life. Homozygosity for the 4G allele, despite its association with impaired fibrinolysis, is compatible with successful aging.
Plasma LDL and HDL Subspecies Are Heterogenous in Particle Content of Tocopherols and Oxygenated and Hydrocarbon Carotenoids
Authors: Goulinet Sylvie , Chapman M. John
Published: June 2011

Abstract
Epidemiological data indicate that dietary tocopherols and carotenoids can exert cardioprotective effects, which may be mediated by their antioxidant actions. The oxidative modification of LDL underlies the atherogenicity of these cholesterol-rich particles. The resistance of LDL to oxidation is influenced by several endogenous factors, among which the content of tocopherols and carotenoids is prominent. Of the exogenous factors, HDL inhibits oxidation of LDL via several mechanisms. In view of the paucity of data on the distribution of diverse tocopherol and carotenoid components among the apoB- and apoA-I–containing lipoproteins of human plasma, we evaluated the quantitative and qualitative features of the LDL and HDL particle subspecies in normolipidemic subjects. The bulk of tocopherols and hydrocarbon carotenoids (lycopene, α- and β-carotene) was transported in LDL (45% and 76%, respectively), in contrast to the oxygenated carotenoids (lutein/zeaxanthin, canthaxanthin, and β-cryptoxanthin), which were equally distributed between LDL and HDL. α-Tocopherol content was independently associated with lipid core size (cholesteryl ester and triglyceride) in VLDL, LDL, and HDL (
P
<.005); by contrast, the particle content of the oxygenated carotenoids lutein/zeaxanthin and canthaxanthin was strongly related to that of phospholipids. A significant and progressive decrease in the molar content of α- and γ-tocopherols was found with increase in density from light to dense LDL subspecies (LDL1 to LDL5); a similar trend was observed in HDL subspecies. Furthermore, particle contents of lutein/zeaxanthin, β-cryptoxanthin, β-carotene, and lycopene were markedly reduced in small, dense LDL (LDL5,
d
=1.050 to 1.065 g/mL). We conclude that diminished contents in such carotenoids as well as in tocopherols could underlie not only the diminished oxidative resistance of small, dense LDL but also reduced tissue targeting of antioxidants in subjects with a dense LDL phenotype.
Differences in the Phenotype Between Children With Familial Defective Apolipoprotein B-100 and Familial Hypercholesterolemia
Authors: Pimstone Simon N. , Defesche Joep C. , Clee Susanne M. , Bakker Henk D. , Hayden Michael R. , Kastelein John J.P.
Published: June 2011

Abstract
Familial defective apolipoprotein B-100 (FDB) is a dominantly inherited genetic disorder resulting from a point mutation in the apolipoprotein (apo) B gene and is associated with significantly elevated plasma total and LDL cholesterol levels. Despite numerous descriptions outlining the phenotype of children with familial hypercholesterolemia (FH), no study has described the biochemical and clinical phenotype in a cohort of children with FDB. The phenotypes of FH and FDB, therefore, have not been compared in children. We have studied a cohort of 38 Dutch children (all <20 years old) with FDB from 21 different families. Lipid and lipoprotein levels and the clinical phenotype were compared with 97 age-matched FH heterozygotes, as defined by molecular analysis, and with age-matched non-FDB, non-FH control subjects. Female FDB carriers (n=23) had significantly lower total cholesterol (
P
<.001), LDL cholesterol (
P
=.001), total cholesterol:HDL ratio (
P
<.001), and apoB levels (
P
=.001) than age-matched female FH heterozygotes (n=50). Similar results were noted in male FDB carriers (n=15) compared with male FH heterozygotes (n=47;
P
=.005,
P
=.007,
P
=.014, and
P
=.074, respectively). Within the FDB group, female FDB heterozygotes had higher LDL cholesterol (
P
=.038) and a trend to higher total cholesterol levels (
P
=.165) than age-matched males. Both male and female FDB carriers had significantly higher total cholesterol, LDL cholesterol, and total cholesterol:HDL ratio than age- and sex-matched control subjects, which was evident even in children <10 years of age, providing additional evidence that this mutation is penetrant in early life. These results provide evidence for a milder biochemical phenotype in children with FDB than in children with FH. The phenotype observed is intermediate between that of control subjects and FH heterozygotes matched for age and sex. As the incidence of coronary artery disease is related to both the extent and duration of cholesterol elevation, our findings might explain in part the lower incidence of clinical atherosclerosis seen in adults with this condition than in adults with FH.
Segregation Analysis of Plasma Apolipoprotein B Levels in Familial Combined Hyperlipidemia
Authors: Bredie S.J.H. , van Drongelen J. , Kiemeney L.A. , Demacker P.N.M. , Beaty T.H. , Stalenhoef A.F.H.
Published: June 2011

AbstractFamilial combined hyperlipidemia (FCH) is a heritable lipid disorder that is associated with an increased risk of premature cardiovascular disease. An elevated plasma apolipoprotein (apo) B concentration is reported to be a diagnostic feature of the disorder. Recently we demonstrated a strong relation between plasma apoB concentrations and the cholesterol concentration in VLDL plus LDL, both elevated in FCH families. Therefore, examination of the inheritance of elevated plasma apoB levels in FCH families may reveal important information about the mechanism responsible for the aggregation of elevated plasma lipids in FCH. This study included 663 Dutch family members in 40 families ascertained through FCH probands. Plasma apoB concentration correlated significantly with apoB-related cholesterol both in the probands and the relatives (r=.83 andr=.90, respectively). Adjustment for age, sex, body mass index, and smoking habits accounted for 35.7% of the variation in apoB levels, and there was strong familial aggregation in adjusted apoB levels in these families. Complex segregation analysis was performed to determine the mechanism of inheritance behind this familial aggregation. The aggregation of elevated apoB levels was best explained by a major gene effect inherited by a codominant mechanism. Estimated mean apoB levels for the three supposed genotypes AA, AB, and BB were 111.5, 126.7, and 165.7 mg/dL, respectively, with relative frequencies of 43.5%, 44.9%, and 11.6%, respectively. In conclusion, despite assumed metabolic and genetic heterogeneity of FCH, there is clear evidence for a single gene effect on apoB concentrations in families ascertained through FCH. Linkage studies based on this analysis may further clarify the molecular basis of the apoB regulation in these families.
The Apolipoprotein E2(Arg145Cys) Mutation Causes Autosomal Dominant Type III Hyperlipoproteinemia With Incomplete Penetrance
Authors: de Villiers Willem J.S. , van der Westhuyzen Deneys R. , Coetzee Gerhard A. , Henderson Howard E. , Marais A. David
Published: June 2011

Abstract
Type III hyperlipoproteinemia (type III HLP) is an atherogenic disorder of lipoprotein metabolism characterized by the accumulation of cholesterol-enriched VLDL and is usually associated with homozygosity for a normal variant of apoE, apoE2. ApoE2(Arg145Cys) is a rare variant arising from a C→T transition at nucleotide 4031 and has been linked to type III HLP. Ten subjects from a group of 42 unrelated individuals with proven type III HLP were found to be either heterozygous or homozygous for the apoE2(Arg145Cys) mutation by DNA sequencing. The apoE4-Philadelphia (Glu13Lys, Arg145Cys) variant was subsequently excluded. None of 4 homozygotes (3 blacks and 1 of mixed ancestry) developed ischemic heart disease, but they did present with xanthomata. In contrast, 6 heterozygous subjects presented mainly with ischemic heart disease but generally lacked physical signs. Cholesterol concentrations ranged from 6.2 mmol/L to 13.3 mmol/L and triglyceride levels from 3.2 to 13.2 mmol/L. The dyslipoproteinemia in homozygous and heterozygous subjects was indistinguishable. Family investigation identified an additional 10 heterozygous mutant-allele carriers, of whom 3 had type III HLP. This unique cohort of patients indicates that the apoE2(Arg145Cys) mutation is relatively common in several population groups in our region and may be particularly prevalent in blacks. There was no clear allele dosage effect present for the development of dyslipoproteinemia or atherosclerosis. The mode of inheritance is for the first time clearly established to be autosomal dominant with incomplete penetrance.
Adenovirus-Mediated Transfer of a Dominant-Negative H-
ras
Suppresses Neointimal Formation in Balloon-Injured Arteries In Vivo
Authors: Ueno Hikaru , Yamamoto Hiroaki , Ito Shin-ichi , Li Jian-Jun , Takeshita Akira
Published: June 2011

Abstract
Abnormal migration and proliferation of arterial smooth muscle cells may be a central event in inflammatory proliferative arterial diseases such as atherosclerosis and restenosis after angioplasty. The proto-oncogene c-H-
ras
is considered to be a key transducer in various growth-signaling events. We constructed an adenoviral vector (AdexCAHRasY57) expressing a potent dominant-negative mutated form of c-H-
ras
in which tyrosine replaces aspartic acid at residue 57. Infection of smooth muscle cells with AdexCAHRasY57 produced a large quantity of H-
ras
-p21, completely inhibited serum-stimulated activation of mitogen-activated protein kinase, and abolished the DNA synthesis in response to serum mitogens. However, a surge of intracellular Ca
2+
concentration in response to platelet-derived growth factor was not affected, suggesting that some cellular functions were preserved. When we applied AdexCAHRasY57 into balloon-injured rat carotid arteries from inside the lumen, neointimal formation was significantly reduced (neointima/media ratio: 0.28) compared with that (1.50) in arteries treated with either injury alone or injury and infection with a control adenovirus, AdexCALacZ, expressing bacterial β-galactosidase. Our results suggest that adenovirus-mediated arterial transfer of dominant-negative H-
ras
may be a practical form of effective molecular intervention for proliferative arterial diseases.
In Vivo Transfer of Lipoprotein(a) Into Human Atherosclerotic Carotid Arterial Intima
Authors: Nielsen Lars B. , Grønholdt Marie L.M. , Schroeder Torben V. , Stender Steen , Nordestgaard Børge G.
Published: June 2011

Abstract
The aim of this study was to compare the atherogenic potential of lipoprotein(a) [Lp(a)] and LDL by measuring the intimal clearance of these two plasma lipoproteins in the atherosclerotic intima of the human carotid artery in vivo. Autologous
131
I-Lp(a) and
125
I-LDL were mixed and reinjected intravenously 3 hours before elective surgical removal of the arterial intima in four patients. The intimal clearance of Lp(a) and LDL was 229±48 and 405±127 nL/cm
2
per hour, respectively (paired
t
test;
P
=.12). The mass accumulation of Lp(a) (114±32 ng/cm
2
per hour) was on average one 15th that of LDL (paired
t
test;
P
=.06), mainly reflecting a low plasma concentration of Lp(a) compared with LDL in the human subjects studied. In accordance with our previous observation in rabbits, there was a positive association between the intimal clearance of LDL and that of Lp(a) (
r
=.97,
P
=.03). Accordingly, high plasma levels of Lp(a) may share with LDL the potential for causing lipid accumulation in the arterial intima in humans.
Relative Involvement of GPIb/IX-vWF Axis and GPIIb/IIIa in Thrombus Growth at High Shear Rates in the Guinea Pig
Authors: André Patrick , Hainaud Patricia , Bal dit Sollier Claire , Garfinkel Leonard I. , Caen Jacques P. , Drouet Ludovic O.
Published: June 2011

Abstract
The relative involvement of the glycoprotein (GP) Ib/IX–von Willebrand factor (vWF) axis and GPIIb/IIIa in thrombus growth at high shear rates was assessed and compared by testing the pharmacological effects of VCL, a recombinant GPIb-binding fragment of vWF (residues 504-728), aurintricarboxylic acid (ATA), which binds to the 509-695 disulfide loop of vWF, and lamifiban, a specific synthetic GPIIb/IIIa antagonist. In vivo, their effects were evaluated in guinea pig mesenteric arteries, in a model of a laser-induced cyclic thrombotic process, and ex vivo, at a shear rate of 1800 s
−1
, in a capillary perfusion chamber model, in which collagen-adherent platelets are exposed to nonanticoagulated guinea pig blood. In vivo, VCL, ATA, and lamifiban administered 2 minutes after intimal injuries stopped thrombus growth, prevented the cyclic thrombotic process, and induced gradual thrombus dissolution. Ex vivo, at 1800 s
−1
, collagen exposure to untreated blood for 2 minutes, 4 minutes, or two consecutive periods of 2 minutes each resulted in similar platelet adhesion, 56%, 59%, and 61%, respectively, with an average thrombus volume of 6, 19, and 17.5 μm
3
/μm
2
, respectively, without any fibrin formation. This indicated that the two consecutive perfusions did not affect the dynamic process of thrombus growth. When collagen-adherent platelets deposited after the first 2-minute perfusion were perfused for 2 minutes with VCL-, ATA-, or lamifiban-treated blood, thrombus growth was prevented and platelet adhesion remained unchanged, but fibrin formation increased on and around the predeposited platelets. These results suggest that both the GPIb/IX-vWF axis and GPIIb/IIIa are involved in in vivo platelet-to-platelet interactions at high shear rates in the guinea pig.
Plasma Total Homocysteine, B Vitamins, and Risk of Coronary Atherosclerosis
Authors: Verhoef Petra , Kok Frans J. , Kruyssen Dick A.C.M. , Schouten Evert G. , Witteman Jacqueline C.M. , Grobbee Diederick E. , Ueland Per M. , Refsum Helga
Published: June 2011

Abstract
Epidemiological research has shown that elevated plasma total homocysteine (tHcy) is a risk factor for atherosclerotic disease. In the present case-control study, we investigated whether fasting or postmethionine-loading tHcy was a stronger predictor of risk of severe coronary atherosclerosis. Furthermore, we studied levels of B vitamins, which are involved in homocysteine metabolism. Subjects were recruited from men and women, aged 25 to 65 years, who underwent coronary angiography between June 1992 and June 1994 in a hospital in Rotterdam, The Netherlands. Cases (n=131) were defined as those with ≥90% occlusion in one and ≥40% occlusion in a second coronary artery, while control subjects (n=88) had ≤50% occlusion in only one coronary vessel. In addition, a population-based control group free from clinical cardiovascular disease (n=101) was studied. Coronary patients were studied at least 2.5 months after angiography or other acute illness, such as myocardial infarction. After adjusting for age and sex differences between the groups, cases had 9% (
P
=.01) higher geometric mean fasting and 7% (
P
=.04) higher geometric mean postload tHcy than the combined control groups. Despite higher levels of tHcy for cases, their geometric mean levels of red cell folate and pyridoxal 5′-phosphate were higher than for control subjects, whereas plasma vitamin B
12
was only slightly lower in cases. The frequency distribution of tHcy values in cases was slightly shifted toward the right, across the entire range, compared with the distribution in the combined control group. This was somewhat more obvious for fasting than postload tHcy levels. The odds ratio (OR) for severe coronary atherosclerosis (case status) for each 1 SD increase in fasting tHcy (5 μmol/L) was 1.3 (95% confidence interval [CI], 1.0-1.6), similar to the OR for each 1 SD increase (12 μmol/L) in postmethionine-loading tHcy (1.3 [95 CI, 1.0-1.7]), after adjustment for sex, age, and other potential confounders. Furthermore, there was a significant linear trend of increasing fasting tHcy with increasing number of occluded arteries (
P
=.01), correcting for sex, age, and other potential confounders. Our data show a positive association between plasma tHcy and risk of severe coronary atherosclerosis, of similar strength for fasting and postload tHcy levels. The data suggest that the association exists over a wide range of tHcy levels, without a clear cutoff point below which there is no increased risk.
Genetic Polymorphism of Paraoxonase and the Risk of Coronary Heart Disease
Authors: Sanghera Dharambir K. , Saha Nilmani , Aston Christopher E. , Kamboh M. Ilyas
Published: June 2011

AbstractRecent studies have implicated paraoxonase, an HDL-associated enzyme, in providing protection against LDL oxidation, thus affecting the risk of coronary heart disease (CHD) in the general population. In this study, we evaluated the distribution of a biallelicPONpolymorphism at codon 192 (AandBalleles) and its relationship with plasma lipids and CHD in two racial groups comprising Asian Indians and Chinese from Singapore. The frequency of theBallele was significantly higher in Chinese control subjects than in Indian control subjects (0.58 versus 0.33;P<.0001). With the exception of a marginal effect on apolipoprotein A-I levels in Indians, no other significant association was observed between thePONpolymorphism and quantitative lipid traits in either racial group. However, there was a race-specific association of theBallele with CHD in Indians but not in Chinese. The Indian CHD patients had a significantly higher frequency of theBallele than control subjects (.43 versus .33;P=.014). The age- and sex-adjusted odds ratio for developing CHD with theBallele (BB+ABgenotypes) was 2.01 (95% CI, 1.17 to 3.45;P=.011) compared with theAallele (AAgenotype). When the Indian patients were stratified into subgroups, the association remained significant in nondiabetic patients (odds ratio, 2.29;P=.008), and it became stronger in patients with myocardial infarction (odds ratio, 2.94;P=.004) than in patients without myocardial infarction (odds ratio, 1.11;P=.76). These data indicate that a common polymorphism in thePONgene is an independent risk factor for CHD in populations with white ancestry.
Urbanization Elicits a More Atherogenic Lipoprotein Profile in Carriers of the Apolipoprotein A-IV-2 Allele Than in A-IV-1 Homozygotes
Authors: Campos Hannia , López-Miranda José , Rodríguez Carmen , Albajar Marta , Schaefer Ernst J. , Ordovás José M.
Published: June 2011

Abstract
Coronary heart disease (CHD) is increasing in developing countries, particularly in urban areas. The impact of urbanization and apolipoprotein (apo) A-IV genetic polymorphism on plasma lipoproteins was studied in 222 men and 236 women from rural and urban Costa Rica. The apoA-IV allele frequencies were 0.937 for apoA-IV-1 and 0.062 for apoA-IV-2. Significant interactions between the apoA-IV polymorphism and area of residence (rural versus urban) were detected for HDL cholesterol (
P
=.003), apoA-I (
P
=.05), LDL particle size (
P
=.01), and LDL/HDL cholesterol ratio (
P
=.005). Urban compared with rural carriers of the apoA-IV-2 allele had significantly lower plasma HDL cholesterol (0.95 versus 1.17 mmol/L) and apoA-I (980 versus 1140 mg/L), a significantly higher LDL/HDL cholesterol ratio (3.35 versus 2.39), and significantly smaller LDL particles (258 versus 263 Å). In contrast, no significant rural-urban differences for these parameters were found in apoA-IV-1 homozygotes. Regardless of their apoA-IV phenotype, urban residents consumed more saturated fat (
P
=.02) and smoked more cigarettes per day (
P
=.03) than rural residents. A significant interaction between saturated fat intake and apoA-IV phenotype was found for HDL cholesterol (
P
<.0003) and LDL/HDL cholesterol ratio (
P
<.003). Increased saturated fat intake (13.6% versus 8.6% of calories) was significantly associated with 6% higher HDL cholesterol and no change (0.7%) in LDL/HDL cholesterol ratio in apoA-IV-1 homozygotes and with 19% lower HDL cholesterol and 37% higher LDL/HDL cholesterol ratio among carriers of the apoA-IV-2 allele. Smokers (≥1 cigarette per day) had significantly lower HDL cholesterol (
P
<.005) and apoA-I (
P
<.01) concentrations than nonsmokers (<1 cigarette per day), particularly among carriers of the apoA-IV-2 allele (−19% and −13%) compared with apoA-IV-1 (−4% for both). After taking these lifestyle characteristics into account, the areas of residence by phenotype interactions for plasma lipoprotein concentrations were no longer statistically significant. Lifestyles associated with an urban environment, such as increased smoking and saturated fat intake, elicit a more adverse plasma lipoprotein profile among Costa Rican carriers of the apoA-IV-2 allele than in apoA-IV-1 homozygotes. Therefore, under the conditions studied, persons with the apoA-IV-2 allele may be more susceptible to CHD.
Associations of Age, Adiposity, Menopause, and Alcohol Intake With Low-Density Lipoprotein Subclasses
Authors: Williams Paul T. , Krauss Ronald M.
Published: June 2011

AbstractWe used nondenaturing polyacrylamide gradient gel electrophoresis to examine the associations of age, adiposity, menopause, and alcohol intake with LDL subclasses in 355 individuals. The absorbency of protein stain was used as an index of mass concentrations at intervals of 0.05 nm within seven LDL subclasses: LDL-IVB (22.0 to 23.2 nm), LDL-IVA (23.3 to 24.1 nm), LDL-IIIB (24.2 to 24.6 nm), LDL-IIIA (24.7 to 25.5 nm), LDL-II (25.5 to 26.4 nm), LDL-I (26.0 to 28.5 nm), and intermediate-size lipoproteins (ISL, 28.0 to 32.0 nm). Age and alcohol intake were obtained from questionnaires, and body mass index was computed from clinic measurements of weight and height. In adult men, body mass index correlated positively with LDL-III, and alcohol intake correlated positively with larger LDL-I. Age was positively correlated with LDL-IIIA and ISL in both men and women and with LDL-IIIB and LDL-II in women. Postmenopausal women had higher LDL-IIIA, LDL-II, and ISL than both premenopausal and premenarchal females. Adult males, ≥18 years old, had higher levels of LDL-IIIA and LDL-II than younger males. Adjustment for fasting plasma triglyceride levels eliminated the significant associations between age and LDL-IIIA in both men and women and between age and LDL-II in women. Partial correlation analyses showed that reductions in the LDL peak diameter associated with increasing age, male sexual maturation, menopause, and adiposity are attributable to increases in the LDL-IIIA subclass. Thus, densitometric measurements of protein-stained gradient gels reveal specific relationships between LDL subclasses and age, adiposity, and alcohol intake beyond those identified by the LDL peak or average diameter.
Relationship of C-Reactive Protein to Risk of Cardiovascular Disease in the Elderly
Authors: Tracy Russell P. , Lemaitre Rozenn N. , Psaty Bruce M. , Ives Diane G. , Evans Rhobert W. , Cushman Mary , Meilahn Elaine N. , Kuller Lewis H.
Published: June 2011

Abstract
Markers of inflammation, such as C-reactive protein (CRP), are related to risk of cardiovascular disease (CVD) events in those with angina, but little is known about individuals without prevalent clinical CVD. We performed a prospective, nested case-control study in the Cardiovascular Health Study (CHS; 5201 healthy elderly men and women). Case subjects (n=146 men and women with incident CVD events including angina, myocardial infarction, and death) and control subjects (n=146) were matched on the basis of sex and the presence or absence of significant subclinical CVD at baseline (average follow-up, 2.4 years). In women but not men, the mean CRP level was higher for case subjects than for control subjects (
P
≤.05). In general, CRP was higher in those with subclinical disease. Most of the association of CRP with female case subjects versus control subjects was in the subgroup with subclinical disease: 3.33 versus 1.90 mg/L,
P
<.05, adjusted for age and time of follow-up. Case-control differences were greatest when the time between baseline and the CVD event was shortest. The strongest associations were with myocardial infarction, and there was an overall odds ratio for incident myocardial infarction for men and women with subclinical disease (upper quartile versus lower three quartiles) of 2.67 (confidence interval [CI]=1.04 to 6.81), with the relationship being stronger in women (4.50 [CI=0.97 to 20.8]) than in men (1.75 [CI=0.51 to 5.98]). We performed a similar study in the Rural Health Promotion Project, in which mean values of CRP were higher for female case subjects than for female control subjects, but no differences were apparent for men. Comparing the upper quintile with the lower four, the odds ratio for CVD case subjects was 2.7 (CI=1.10 to 6.60). In conclusion, CRP was associated with incident events in the elderly, especially in those with subclinical disease at baseline.
Effects of Short-term Hormone Replacement Therapies on Low-Density Lipoprotein Metabolism in Cynomolgus Monkeys
Authors: Wagner Janice D. , Schwenke Dawn C. , Zhang Li , Applebaum-Bowden Deborah , Bagdade John D. , Adams Michael R.
Published: June 2011

Abstract
Estrogen replacement therapy reduces the risk of coronary heart disease in women and decreases the extent of atherosclerosis in monkeys. In our previous studies, estrogen treatment decreased arterial LDL degradation and accumulation, thus indicating one mechanism by which estrogen inhibits the progression of atherosclerosis. The influence of progestins on these processes remains unclear. The objective of this study was to determine the effects of oral estrogen (conjugated equine estrogens) and progestin (medroxyprogesterone acetate) alone or in combination on arterial LDL metabolism after 12 weeks of atherogenic stimulus. This relatively short period of treatment was chosen to determine effects on arterial LDL metabolism before substantial subendothelial macrophage accumulation. In contrast to previous studies (16 to 18 weeks of treatment), when macrophages were present in the intima, neither estrogen nor progestin (nor their combination) had any effect on any index of arterial LDL metabolism. These results suggest that estrogen may preferentially reduce LDL metabolism in macrophages with little effect on cells of the normal artery. In contrast to arterial LDL metabolism, hepatic LDL uptake was significantly increased in animals treated with estrogen or estrogen plus progestin. Despite the increased LDL uptake by the liver, hepatic lipid content was significantly decreased by ≈50% in both estrogen and estrogen-plus-progestin treatment compared with control and progestin-treated animals. The decrease in hepatic cholesterol content is hypothesized to be due to increased biliary secretion of cholesterol.
Heterogeneity of Endothelial Cells
Authors: Garlanda Cecilia , Dejana Elisabetta
Published: June 2011

AbstractDuring embryonic development, endothelial cells differentiate from a common precursor called angioblast and acquire organ-specific properties. One of the important determinants of endothelial cell differentiation is the local environment, and especially the interaction with surrounding cells. This interaction may occur through the release of soluble cytokines, cell-to-cell adhesion and communication, and the synthesis of matrix proteins on which the endothelium adheres and grows. The acquisition and maintenance of specialized properties by endothelial cells is important in the functional homeostasis of the different organs. For instance, in the brain, alteration of the blood-brain barrier properties may have important consequences on brain functional integrity. One of the major limitations to the study of endothelial cell heterogeneity is the fact that these cells are still difficult to isolate and culture from the microcirculation of different organs, and once in culture, they tend to lose their specialized properties. This finding suggests that we have to develop new culture systems, which possibly include coculture with other cell types. An important issue is to develop tools that can help in recognizing endothelial cells and their differentiated phenotype both in vivo and in tissue culture. In this review we give a short overview of the differentiated properties of the endothelium, considering a few examples of highly specialized endothelial cells, such as the brain or bone marrow microcirculation or high endothelial venules. We made a particular effort to list the most common markers of endothelial cell phenotypes. These molecules and related antibodies may be valuable tools for endothelial cell isolation and characterization.
Effects of Contraceptive Estrogen and Progestin on the Atherogenic Potential of Plasma LDLs in Cynomolgus Monkeys
Authors: Manning James M. , Edwards Iris J. , Wagner William D. , Wagner Janice D. , Adams Michael R. , Parks John S.
Published: June 2011

Abstract
This study was designed to determine the effect of oral contraceptive treatment (estrogen and progestin), alone or in combination, on LDL composition and atherogenic potential in cynomolgus monkeys fed an atherogenic diet. Groups (n=8 each) of monkeys were untreated (control) or treated with ethinyl estradiol (EE), levonorgestrel (LNG), or triphasic oral contraceptive (EE+LNG) for 1.5 years before plasma LDLs were isolated for characterization. Total plasma cholesterol concentrations were unaffected by the treatments. LDL particle size (measured as LDL molecular weight, g/μmol) was significantly smaller in the EE (4.61±0.09) and EE+LNG (4.43±0.09) treatment groups compared with the control (4.99±0.09) or LNG (5.29±0.17) groups and contained fewer molecules of free and esterified cholesterol. Both the EE and EE+LNG groups had significantly less cholesterol and apolipoprotein B distributed in the
d
=1.015 to 1.025 g/mL subfraction and correspondingly more in the
d
=1.025 to 1.035 g/mL subfraction of LDL compared with the control and LNG groups. The apolipoprotein E content (molecules/particle) of LDL was significantly less in the EE (0.35±0.1) and EE+LNG (0.28±0.1) groups compared with the control (0.86±0.2) and LNG (0.99±0.2) groups, and this trend was apparent in all three LDL subfractions. The atherogenic potential of LDL was tested using an in vitro binding assay to arterial proteoglycans. Twice as much LDL bound to arterial proteoglycans in the LNG group (11.3±1.8% of total LDL cholesterol in the incubation) compared with the control (6.4±1.9%), EE (5.5±1.5%), or EE+LNG (5.2±1.2%) groups. We conclude that EE and EE+LNG treatment alters the composition of LDL toward a less atherogenic particle that is smaller and more dense, contains less cholesterol and less apolipoprotein E, and is less reactive with arterial proteoglycans compared with LNG treatment. The inclusion of EE in the triphasic oral contraceptive treatment was sufficient to negate the potentially atherogenic effects of LNG on LDL composition.

(Arterioscler Thromb Vasc Biol. 1997;17:1216-1223.)
Low-Affinity Thromboxane Receptor Mediates Proliferation in Cultured Vascular Smooth Muscle Cells of Rats
Authors: Ko Feng N.
Published: June 2011

Abstract
We examined the binding properties and mitogenic effects of U46619, using cultured vascular smooth muscle cells (VSMCs), by ligand-binding assay, measuring [
3
H]thymidine and [
3
H]leucine incorporation, checking with flow cytometry, and counting the cell number. The U46619-activated mitogenic signal-transduction pathway was assessed by mea-suring formation of inositol monophosphate (IP); [Ca
2+
]
i
; mitogen-activated protein kinase (MAPK), MAPK kinase (MAPKK), and p74raf-1 activities; and GTP-bound Ras. [
3
H]U46619 bound to cultured VSMCs from Wistar-Kyoto (WKY) rats at a single class of site
(K
d
: 15.5±2.6 nmol/L). However, it bound to VSMCs from spontaneously hypertensive rats (SHRs) at two classes of sites (
K
d
: 2.3±0.6 nmol/L and 1.4±0.5 μmol/L). U46619 increased DNA and protein synthesis, cell number, IP formation, [Ca
2+
]
i
, and MAPK and MAPKK activities, with EC
50
values close to its
K
d
value for the low-affinity binding site in VSMCs from SHR. Prostaglandin (PG) E
2
and PGF
2α
showed little of such mitogenic effects. All these effects of U46619 were inhibited by SQ29548, staurosporine, or pretreatment of VSMCs with phorbol 12-myristate 13-acetate for 24 hours. However, U46619 stimulation did not lead to a significant increase in the Ras-GTP complex or p74raf-1 activity. In conclusion, the mitogenic effect of U46619 appears to be mediated via the activation of low-affinity thromboxane binding sites that trigger phosphoinositide hydrolysis and activate the MAPK pathway, leading to DNA synthesis and cell proliferation.
In Vivo/In Vitro Comparison of Rat Abdominal Aorta Wall Viscosity
Authors: Boutouyrie Pierre , Bézie Yvonnick , Lacolley Patrick , Challande Pascal , Chamiot-Clerc Philippe , Benetos Athanase , Renaud de la Faverie Jean François , Safar Michel , Laurent Stéphane
Published: June 2011

AbstractArterial wall viscosity (AWV) is a potential source of energy dissipation in circulation. That arteries, which are known to be markedly viscous in vitro, have lower viscosity in vivo has been suggested but not demonstrated under similar pressure conditions. Endothelium, which may modulate AWV through smooth muscle tone, could contribute to the low level of viscosity in vivo. Our objectives were first to compare AWV of the rat abdominal aorta, in vivo and in vitro, with similar pulse-pressure waves, and second, to determine whether endothelial function influences AWV in vivo and in vitro. The diameter of the abdominal aorta and distending pressure were measured in vivo and in vitro with a high-resolution echotracking system and a micromanometer, respectively. AWV was calculated as the area of the pressure-volume curve hysteresis. After in vivo examination, the arterial segments were isolated in vitro and submitted to resynthesized pressure waves identical to those recorded in vivo. Deendothelialization was performed in vivo by balloon rubbing; then arteries were examined either in vivo or in vitro. AWV was markedly lower in vivo than in vitro (6.6±0.7 versus 22.7±3.7 J · m−1· 10−5, respectively;P<.001). After deendothelialization, a sustained 40% increased AWV was observed during a 15-minute follow-up (P<.01). In vitro, deendothelialized arteries have a 64% higher AWV than segments with endothelium (P<.01). Our results indicate that the physiological effective viscosity, measured in vivo in intact animals, is threefold lower than the intrinsic viscosity of the arterial wall, measured in vitro. Endothelium removal determines a sustained increase in AWV, either in vivo or in vitro. These results suggest that active mechanisms compensate for intrinsic viscosity under physiological conditions. One of these energy-saving mechanisms might be dependent on normal endothelial function.
Deficiency of Inflammatory Cell Adhesion Molecules Protects Against Atherosclerosis in Mice
Authors: Nageh Maged F. , Sandberg Eric T. , Marotti Keith R. , Lin Alice H. , Melchior Earline P. , Bullard Daniel C. , Beaudet Arthur L.
Published: June 2011

AbstractLeukocyte and endothelial cell adhesion molecules (CAMs) are essential for emigration of leukocytes, with the selectins mediating the initial step of leukocyte “rolling” and the β2-(CD18) integrins and intercellular adhesion molecule-1 (ICAM-1) being important for firm adhesion and emigration. On the basis of evidence for an inflammatory component in the pathogenesis of atherosclerosis, including increased expression of CAMs, cytokines, and growth factors, we tested the hypothesis that decreased expression of inflammatory CAMs would reduce susceptibility to atherosclerosis. Using C57BL/6 mice fed a high-fat diet, we observed a 50% to 75% reduction in atherosclerotic fatty streaks in mice with homozygous mutations for ICAM-1, P-selectin, CD18, both ICAM-1 and CD18, or both ICAM-1 and P-selectin. In contrast to previous evidence of increased expression of CAMs in atherosclerotic lesions, which does not prove a cause-and-effect relationship, these data indicate directly that the level of expression of CAMs can determine the susceptibility to the formation of atherosclerotic fatty streaks. The results suggest that genetic variation at these loci could influence susceptibility to atherosclerosis and that pharmacological reduction of the expression or function of these CAMs might protect against atherosclerosis.
Coagulation Factor VII and the Risk of Coronary Heart Disease in Healthy Men
Authors: Junker Ralf , Heinrich Jürgen , Schulte Helmut , van de Loo Jürgen , Assmann Gerd
Published: June 2011

Abstract
Numerous investigations have demonstrated the role of thrombus formation in the pathogenesis of coronary heart disease (CHD). A tendency to thrombosis may also be indicated by elevated levels of coagulation factor VII clotting activity (FVIIc). Significant associations of FVIIc with increased coronary risk, however, have been found only in the Northwick Park Heart Study. Here we present the results of the 8-year follow-up of FVIIc measurements in 2780 healthy men of the Prospective Cardiovascular Münster study. In the study population (age at entry, 49.3±6.1 years, mean±SD), 130 CHD events occurred during follow-up. FVIIc was significantly higher in subjects with coronary events than in those without (112.4±20.1% vs 108.7±21.4%,
P
=.023). Compared with individuals without coronary events, FVIIc was not significantly higher in men with nonfatal events (111.7±20.4%;
P
=.196, n=93), but there was a tendency toward higher FVIIc activity in subjects with fatal events (114.6±19.5%;
P
=.076, n=37). In the multiple logistic regression analysis, we did not find FVIIc to be an independent risk factor for CHD, and the significance of FVIIc disappeared after total cholesterol, LDL-cholesterol, and triglycerides were taken into account. The increase in the number of CHD events through higher levels of FVIIc was more pronounced in the presence of additional cardiovascular risk factors: smoking; myocardial infarction events in family; angina pectoris; high levels of fibrinogen, total cholesterol, LDL cholesterol, and triglycerides; and a low level of HDL cholesterol. We conclude that FVIIc is a risk factor for CHD, especially in the presence of additional risk factors, and must be taken into account when assessing cardiovascular risk in men.
Lipid Binding of Apolipoprotein CII Is Required for Stimulation of Lipoprotein Lipase Activity Against Apolipoprotein CII–Deficient Chylomicrons
Authors: Olivecrona Gunilla , Beisiegel Ulrike
Published: June 2011

Abstract
Human apolipoprotein CII (apo CII) consists of 79 amino acid residues. The amino-terminal two thirds of the molecule binds to lipid through the formation of amphipathic helixes, while the carboxy-terminal third is engaged in activation of lipoprotein lipase (LPL). On the basis of studies in model systems, it was previously concluded that fragments of apo CII spanning residues 51-79 were sufficient for activation, although they do not bind to lipid. In the present study, we used chylomicrons from an apo CII–deficient patient to reinvestigate this possibility, with a physiologically relevant substrate. Human LPL expressed very low activity against these chylomicrons. Addition of apo CII caused an immediate >100-fold increase in lipase activity. The apo CII fragment 50-79 caused very little stimulation, though with some synthetic lipid substrates, this fragment was fully effective. LPL bound to the chylomicrons even in the absence of apo CII but apparently in a nonproductive manner. In accord with this finding, the main effect of apo CII was on the V
MAX
for the reaction, with little or no change in the apparent
K
M.
We conclude that the lipid-binding part of apo CII is needed for activity of LPL against chylomicrons. This idea is in accord with previous studies with lipid monolayers, which showed that the lipid-binding part is necessary for activation of the enzyme at high surface pressures.
Mitochondrial Function Is Involved in LDL Oxidation Mediated by Human Cultured Endothelial Cells
Authors: Mabile Laurence , Meilhac Olivier , Escargueil-Blanc Isabelle , Troly Muriel , Pieraggi Marie-Thérèse , Salvayre Robert , Nègre-Salvayre Anne
Published: June 2011

AbstractHuman endothelial cells (ECs) grown under standard conditions are able to generate a basal level of oxygen free radicals and induce progressive oxidation of LDLs. Inhibition of cell-mediated LDL oxidation by superoxide dismutase, EDTA, or desferrioxamine implicates a role for superoxide anion and/or transition metals in this process. The potential role of the mitochondrion was investigated by inducing mitochondrial deenergization by selective photosensitization or the addition of inhibitors of the mitochondrial respiratory chain. Mitochondria of human cultured ECs were selectively damaged by photosensitization of cells labeled with the mitochondrion-selective fluorescent dye 2-(4-dimethylaminostyryl)-1-methylpyridinium iodide under conditions that induced only low levels of toxicity during the time of the experiment. Photosensitized ECs exhibited severe mitochondrial dysfunction, as suggested by the defect in mitochondrial uptake of the mitochondrion-selective fluorescent dyes [rhodamine 123 and 2-(4-dimethylaminostyryl)-1-methylpyridinium iodide] and morphological alterations as shown by transmission electron microscopy. In mitochondria-photosensitized cells, superoxide anion generation was strongly decreased, as was LDL oxidation and the subsequent cytotoxicity. When ECs were incubated with the mitochondrial respiratory-chain inhibitors antimycin A or rotenone or with the carbonylcyanide-m-chlorophenylhydrazone uncoupler rhodamine 123, uptake and subcellular distribution were altered, and concomitantly superoxide anion production and LDL oxidation were strongly decreased. In conclusion, these data suggest that mitochondrial function is required, directly or indirectly, for the production of superoxide anion and the subsequent LDL oxidation by human vascular ECs.