bluuebunny/crossref_metadata_2025 huggingface dataset:
Carotid Artery Wall Hypertrophy With Age Is Related to Local Systolic Blood Pressure in Healthy Men
Authors: Tanaka Hirofumi , Dinenno Frank A. , Monahan Kevin D. , DeSouza Christopher A. , Seals Douglas R.
Published: June 2011

Abstract
—Carotid artery intima-media thickness (IMT) increases with advancing age in humans. The underlying mechanism of this increase is unknown, but data from animal studies suggest that a chronic increase in local distending pressure can act as a stimulus. To test this hypothesis, we studied a total of 129 healthy normotensive, nonobese, nonsmoking men aged 18 to 77 years. Brachial systolic blood pressure (SBP) was unchanged, but carotid SBP increased progressively with age (
P
<0.05). Carotid IMT and the ratio of carotid IMT to lumen (ultrasonography) increased progressively with age (
P
<0.05). Carotid IMT was ≈50% greater in the older compared with the young men. Carotid SBP was positively related to carotid IMT (
r
=0.55,
P
<0.001). After carotid SBP was taken into account (ANCOVA), the age-related difference in carotid IMT was no longer statistically significant (
P
=0.22). We conclude that carotid IMT increases with age in healthy men in the absence of elevations in peripheral SBP. Carotid SBP increases progressively with advancing age in this population and is significantly related to the corresponding carotid wall hypertrophy. These results support the hypothesis that chronic increases in local distending pressure may be an important mechanism in the wall thickening that occurs with human aging in central elastic arteries.
Chlamydia pneumoniae
Proteins Induce Secretion of the 92-kDa Gelatinase by Human Monocyte– Derived Macrophages
Authors: Vehmaan-Kreula Pirjo , Puolakkainen Mirja , Sarvas Matti , Welgus Howard G. , Kovanen Petri T.
Published: June 2011

Abstract
—
Chlamydia pneumoniae
, an intracellular Gram-negative respiratory bacterium, and macrophages are present in inflammatory tissue sites such as atherosclerotic lesions, where abnormal degradation of the extracellular matrix takes place. To evaluate the potential of
C pneumoniae
for participation in matrix destruction, we studied the effect of this bacterium on the production of 3 matrix-degrading metalloproteinases, 92-kDa gelatinase, interstitial collagenase-1, and stromelysin-1, and their natural inhibitor TIMP-1 (tissue inhibitor of metalloproteinases-1) by human monocyte–derived macrophages differentiated in vitro. Spontaneous production of collagenase and stromelysin by these cells was minimal and was not influenced by
C pneumoniae
. In contrast, the cells secreted substantial basal quantities of 92-kDa gelatinase, the secretion of which was stimulated (on average, 2.5-fold) by
C pneumoniae. C pneumoniae
regulated the expression of 92-kDa gelatinase by macrophages at the pretranslational level. Macrophages secreted only small quantities of TIMP-1. The chlamydial proteins Omp2, MOMP, and HSP60 were also found to participate in the induction of 92-kDa gelatinase by
C pneumoniae
. Denaturation of chlamydial proteins by boiling reduced 92-kDa gelatinase secretion only partially (by 35%), suggesting that the heat-stabile lipopolysaccharide molecules also stimulate secretion of the enzyme. The results show that production of 92-kDa gelatinase by human macrophages is selectively upregulated by
C pneumoniae
, which suggests that these bacteria, when present in a macrophage-containing inflammatory environment, actively participate in the destruction of the extracellular matrix.
Enhanced Superoxide Production in Experimental Venous Bypass Graft Intimal Hyperplasia
Authors: West Nick E. J. , Guzik Tomasz J. , Black Edward , Channon Keith M.
Published: June 2011

Abstract
—Vein graft intimal hyperplasia, due to smooth muscle cell (SMC) proliferation, remains a limiting factor in long-term vein graft patency. Increased superoxide production regulates SMC mitogenesis and contributes to reduced NO bioactivity in systemic models of vascular disease. We compared superoxide production in experimental venous bypass grafts with ungrafted veins and determined its enzymatic sources and cellular localization. Vascular superoxide production was measured in vein grafts and control jugular veins obtained from normocholesterolemic rabbits undergoing jugular vein–carotid artery interposition bypass grafting. Surgical isolation of the contralateral jugular vein, without bypass grafting, provided an additional control for the effects of surgical manipulation. Superoxide production was increased 3-fold in vein grafts compared with control veins. Systematic stimulation and inhibition of specific oxidases revealed that the major source of increased vein graft superoxide production was a membrane-associated NAD(P)H-dependent oxidase. Western blotting of vascular homogenates demonstrated corresponding increases in NAD(P)H oxidase p22
phox
(membrane-associated) and p67
phox
(cytosolic) subunits in vein grafts compared with jugular veins. There was marked intimal hyperplasia in vein grafts, and immunohistochemical staining of vessel cryosections revealed increased p22
phox
-expressing cells in vein grafts that were predominantly intimal SMCs. Superoxide generation is increased in experimental vein grafts compared with ungrafted veins. The principal source of increased superoxide generation in vein grafts is an NAD(P)H oxidase, expressed by intimal SMCs. These findings suggest a role for NAD(P)H oxidase–mediated superoxide production in the proliferative response to vascular injury in vein grafts.
Vascular Cell Adhesion Molecule-1 Augments Adenovirus-Mediated Gene Transfer
Authors: Chu Yi , Heistad Donald D. , Cybulsky Myron I. , Davidson Beverly L.
Published: June 2011

Abstract
—We have reported that adenovirus-mediated gene transfer is augmented in the endothelium of atherosclerotic blood vessels. We observed that vascular cell adhesion molecule-1 (VCAM-1) shares some homology with the coxsackievirus and adenovirus receptor. Because VCAM-1 is upregulated on atherosclerotic endothelial cells, we hypothesized that VCAM-1 may act as an auxiliary receptor to augment adenovirus-mediated gene transfer. To test this hypothesis, stable NIH 3T3 cell lines that constitutively express VCAM-1 on the cell surface were generated. Recombinant adenovirus 5 (Ad5), which contains the reporter β-galactosidase gene, was used to compare Ad5 infection in VCAM-1
+
and parental NIH 3T3 cells. Total β-galactosidase activity and the number of transgene-positive cells were 6- to 10-fold and 5-fold higher, respectively, in VCAM-1
+
than in VCAM-1
−
cells. Ad5 binding to VCAM-1
+
cells was increased by 3-fold over VCAM-1
−
cells. Soluble VCAM-1 protein, present during infection or viral binding, reduced β-galactosidase activity in VCAM-1
+
cells in a dose-dependent manner. Taken together, we conclude that VCAM-1 can mediate adenovirus binding and infection. This may explain, in part, the previous finding that adenovirus-mediated gene transfer is augmented in atherosclerotic arteries.
Localization of Human ATP-Binding Cassette Transporter 1 (ABC1) in Normal and Atherosclerotic Tissues
Authors: Lawn Richard M. , Wade David P. , Couse Tracey L. , Wilcox Josiah N.
Published: June 2011

Abstract
—The present study examines the expression of ATP-binding cassette transporter 1 (ABC1) mRNA in normal and atherosclerotic tissues by using in situ hybridization in an effort to better understand the function of this cholesterol transport protein. Samples of normal baboon tissues as well as human normal and atherosclerotic aortas were hybridized with
35
S-labeled ABC1 sense and antisense riboprobes. Widespread expression of ABC1 was observed generally in tissues containing inflammatory cells and lymphocytes. Other noninflammatory cells that were also sites of ABC1 synthesis included the ductal cells of the kidney medulla, Leydig cells in the testis, and glial cells in the baboon cerebellum. Although normal veins and arteries did not express ABC1 mRNA, it was found to be upregulated in the setting of atherosclerosis, where widespread expression was found in macrophages within atherosclerotic lesions. These results are consistent with the proposed role of ABC1 in cholesterol transport in inflammatory cells. The specific upregulation of ABC1 mRNA in the setting of atherosclerosis probably reflects the response of leukocytes to cholesterol loading. However, the presence of ABC1 in ductal cells of the kidney medulla and in the small intestine suggest a more general role for this protein in cholesterol transport in other cell types.
Paraoxonase1-192 Polymorphism Modulates the Nonfatal Myocardial Infarction Risk Associated With Decreased HDLs
Authors: Sentí Mariano , Tomás Marta , Marrugat Jaume , Elosua Roberto
Published: June 2011

Abstract
—Serum paraoxonase1 (PON1), a high density lipoprotein (HDL)-linked enzyme, appears to have a role in the protection of low density lipoproteins from oxidative stress. PON1 enzyme activity for paraoxon as a substrate is modulated, along with others at the PON1 locus, by the PON1-192 polymorphism, which contains low paraoxon–activity and high paraoxon–activity alleles (Q and R, respectively). The association of PON1 with HDL suggests that impaired serum concentrations of the lipoprotein could have consequences for the susceptibility to oxidative stress. Because PON1-192 polymorphism strongly influences PON1 activity toward paraoxon, we tested the hypothesis that this polymorphism may modulate the myocardial infarction (MI) risk associated with low HDL cholesterol concentrations. Two hundred eighty consecutive MI patients and 396 control subjects were studied. When considered as a whole, PON1-192 genetic polymorphism was not associated with higher MI risk. In the entire population, decreased HDL cholesterol concentration (<0.90 mmol/L in men and <1.11 mmol/L in women) conferred an MI risk of 2.56 (
P
=0.0001) compared with normal HDL levels. The risk increased to 4.51 (
P
<0.0001) in QQ homozygous HDL-deficient subjects relative to QQ homozygotes with normal HDL levels, decreased to 1.83 (
P
=0.1046) in QR heterozygote HDL-deficient subjects, and also decreased (to 1.41,
P
=0.6243) in RR homozygote HDL-deficient individuals compared with RR carriers with normal HDL cholesterol concentration. The effect of PON1-192 genotypes on the association of low HDL cholesterol levels and MI was related to gene dosage. A significantly decreased enzyme activity was found in HDL-deficient MI patients compared with HDL-deficient control subjects (median 208 U/L [interquartile range 136 to 298 U/L] versus median 235 U/L [interquartile range 163 to 350 U/L], respectively;
P
=0.025]. QQ homozygous MI patients showed the greatest difference of PON1 activity levels between normal and HDL-deficiency state groups (14.9%,
P
=0.002). Our observations raise the question of whether the decrease in PON1 activity and the MI risk associated with HDL deficiency are more evident in the low paraoxon–activity QQ genotype. It can be argued that the low paraoxon–activity QQ genotype, which may be adequate to prevent lipid peroxidation in normolipidemic subjects, may be insufficient when an HDL-deficiency state and low PON1 activity reflecting oxidative stress coexist. The risk of nonfatal MI is increased in HDL-deficiency states, principally among subjects carrying the low paraoxon–activity QQ genotype.
Influence of Plasma Fibrinogen Levels on the Incidence of Myocardial Infarction and Death Is Modified by Other Inflammation-Sensitive Proteins
Authors: Lind P. , Hedblad B. , Stavenow L. , Janzon L. , Eriksson K. F. , Lindgärde F.
Published: June 2011

Abstract
—Inflammation may play an important role in atherosclerotic disease. Plasma fibrinogen is an established predictor of cardiovascular events. The aim of this study was to evaluate whether other inflammation-sensitive plasma proteins modify this prediction. We studied the incidence of cardiac events and death in men in relation to fibrinogen levels alone and in combination with other proteins. The study was based on 6075 men, who were, on average, 46 years old at the time of the screening examination, which included the quantitative assessment of plasma levels of fibrinogen, orosomucoid, α
1
-antitrypsin, haptoglobin, and ceruloplasmin. The concentration of each protein was divided into quartiles for each. This classification made it possible to identify 4 groups, ie, men in the first fibrinogen quartile and at the same time either not belonging to the fourth quartile of any of the other proteins (Q1/No group) or also belonging to the fourth quartile of ≥1 of the additional proteins (Q1/Yes group) and corresponding groups in the fourth fibrinogen quartile (Q4/No and Q4/Yes groups). During the follow-up, which occurred at an average of 16 years, 439 (7.2%) men experienced a cardiac event, and 653 (10.7%) died; 278 of these men died of cardiovascular diseases, with 206 deaths attributed to ischemic heart disease. From the lowest to the highest quartile, there was for each protein a stepwise increase in the incidence of cardiac events and mortality. All-cause mortality and cardiovascular mortality were significantly higher in the Q4/Yes group compared with the Q4/No group, but they were similar in the Q4/No and Q1/Yes groups. The incidence of cardiac events was significantly higher in the Q1/Yes and Q4/Yes groups compared with the Q1/No and Q4/No groups, respectively. The increased cardiovascular mortality and cardiac event rates remained after adjustment for several confounders when the Q4/Yes and Q4/No groups were compared. The results suggest that the incidence of cardiac events and death due to cardiovascular diseases in middle-aged men predicted by plasma levels of fibrinogen is modified by other inflammation-sensitive proteins.
Network of Vascular-Associated Dendritic Cells in Intima of Healthy Young Individuals
Authors: Millonig G. , Niederegger H. , Rabl W. , Hochleitner B. W. , Hoefer D. , Romani N. , Wick G.
Published: June 2011

Abstract
—In earlier studies, our group has established a new “immunological” hypothesis for atherogenesis supported by experimental and clinical studies showing that inflammatory immunological reactions against heat shock protein 60 initiate the development of atherosclerosis. In the present study, we describe the discovery of a so-far-unknown network of dendritic cells in the innermost layer of arteries, the intima, but not veins of healthy humans and rabbits. The number of these dendritic cells is comparable to that of Langerhans cells in the skin, and dendritic cells show a similar phenotype (CD1a
+
S-100
+
lag
+
CD31
−
CD83
−
CD86
−
and no staining for von Willebrand factor or smooth muscle cell myosin). These vascular-associated dendritic cells accumulate most densely in those arterial regions that are subjected to major hemodynamic stress by turbulent flow conditions and are known to be predisposed for the later development of atherosclerosis. These results open new perspectives for the activation of the immune system within the arterial wall.
Mast Cell Chymase Induces Apoptosis of Vascular Smooth Muscle Cells
Authors: Leskinen Markus , Wang Yenfeng , Leszczynski Dariusz , Lindstedt Ken A. , Kovanen Petri T.
Published: June 2011

Abstract
—In human coronary atheromas, the numbers of degranulated mast cells and of apoptotic smooth muscle cells (SMCs) are increased. Accordingly, the possibility exists that mast cells participate in the regulation of SMC apoptosis in the lesions. Mast cells isolated from the serosal cavities of rats were stimulated to release their secretory granules. The neutral protease chymase, present in the exocytosed granules, was found to induce apoptosis when added to rat aortic SMCs in culture. The chymase-induced apoptosis of SMCs was detected by flow cytometry, microscopic analysis of cellular morphology, terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL), and electrophoretic demonstration of DNA laddering. Chymase induced SMC apoptosis in a dose- and time- dependent manner, and its proteolytic activity was essential for the proapoptotic effect. In addition to rat chymase, recombinant human chymase was also found to induce apoptosis of human coronary artery SMCs in culture. These results suggest that mast cells may participate in the apoptotic regulation of SMCs in atherosclerotic lesions.
Microsatellite Mutation of Type II Transforming Growth Factor-β Receptor Is Rare in Atherosclerotic Plaques
Authors: Clark Katherine J. , Cary Nathaniel R. , Grace Andrew A. , Metcalfe James C.
Published: June 2011

Abstract
—A somatic mutation within a microsatellite polyA tract in the coding region of the type II transforming growth factor (TGF)-β receptor gene was reported to occur in human atherosclerotic and restenotic lesions. This mutation occurs frequently in colorectal cancer with the replication error repair phenotype and results in loss of sensitivity to the growth inhibitory effects of TGF-β in cells from the tumors. The mutation was proposed to account for the clonal expansion of vascular smooth muscle cells observed in atherosclerotic plaques, through loss of the growth inhibitory effect of TGF-β. The frequency of the mutation and the extent of clonal expansion of the mutated cells have major implications for the mechanism of atherogenesis and therapeutic strategies. We analyzed a set of 22 coronary arterial and 9 aortic samples containing early to advanced atherosclerotic lesions for the mutation in the type II TGF-β receptor polyA tract. Only 1 coronary arterial sample from an advanced lesion showed detectable amounts of the mutation, present at a low level (8% of the DNA sample). The data imply that the mutation occurs only at low frequency and is not a major mechanistic contributor to the development of atherosclerosis.
Relationship of Insulin Sensitivity and ApoB Levels to Intra-abdominal Fat in Subjects With Familial Combined Hyperlipidemia
Authors: Purnell Jonathan Q. , Kahn Steven E. , Schwartz Robert S. , Brunzell John D.
Published: June 2011

Abstract
—Familial combined hyperlipidemia (FCHL) is one of the most common familial dyslipidemias associated with premature heart disease. Subjects with FCHL typically have elevated apolipoprotein B (apoB) levels, variable elevations in cholesterol and/or triglycerides, and a predominance of small, dense, low density lipoprotein particles. It is thought that insulin resistance is important in the expression of the combined hyperlipidemia phenotype. To further characterize the relationship between insulin resistance and increased apoB levels, 11 subjects from well-characterized FCHL families and normal control subjects matched for weight and/or age underwent measurement of intra-abdominal fat (IAF) and subcutaneous fat (SQF) by CT scan, insulin sensitivity (Si) by the frequently sampled intravenous glucose tolerance test, and lipoprotein levels. Body mass index and IAF were higher and Si was lower (more insulin resistant) in the FCHL group than in the age-matched group, but the values were similar in the FCHL group and the age- and weight-matched control group. When the relationship between body fat distribution and Si was tested with multiple linear regression, only IAF was significantly correlated with Si after the addition of SQF and body mass index as independent variables. For any level of insulin sensitivity or IAF, however, apoB levels remained higher in the FCHL subjects than in the control groups. In conclusion, in FCHL, visceral obesity is an important determinant of insulin resistance. Visceral obesity and insulin resistance, however, do not fully account for the elevated levels of apoB in this disorder, and this study provides physiological support for separate, but additive, genetic determinants in the etiology of the lipid phenotype.
Retinoids Inhibit Proliferation of Human Coronary Smooth Muscle Cells by Modulating Cell Cycle Regulators
Authors: Wakino Shu , Kintscher Ulrich , Kim Sarah , Jackson Simon , Yin Fen , Nagpal Sunil , Chandraratna Roshantha A. S. , Hsueh Willa A. , Law Ronald E.
Published: June 2011

Abstract
—Retinoids inhibit rat vascular smooth muscle cell (VSMC) proliferation in vitro and intimal hyperplasia in vivo. We examined the mechanism of the antiproliferative effect of retinoids on human coronary artery smooth muscle cells (human CASMCs). The RAR ligands all-
trans
-retinoic acid (atRA) and ethyl-
p
-[(
E
)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-propenyl]-benzoic acid (TTNPB); a pan-RXR/RAR agonist, 9-
cis
-retinoic acid (9cRA); and the RXR-selective ligand AGN4204 all inhibited DNA synthesis stimulated with platelet-derived growth factor and insulin (IC
50
: TTNPB 63 nmol/L, atRA 120 nmol/L, AGN4204 460 nmol/L, 9cRA 1.5 μmol/L). All retinoids blocked cell cycle progression as determined by flow cytometry and inhibited retinoblastoma protein (Rb) phosphorylation. TTNPB, atRA, and AGN4204 inhibited the mitogenic induction of cyclin D1, whereas 9cRA had no effect. None of the retinoids affected the expression of CDK 2, 4, or 6 or cyclin E. All retinoids attenuated mitogen-induced downregulation of CDKI p27
Kip1
, a major negative regulator of Rb phosphorylation, partly through stabilizing p27
Kip1
turnover. These data demonstrate that retinoids have antiproliferative activity by modulating G
1
→ S cell cycle regulators in human CASMCs through inhibition of Rb phosphorylation and elevation of p27
Kip1
levels.
Determinants of Variable Response to Statin Treatment in Patients With Refractory Familial Hypercholesterolemia
Authors: O’Neill Frans H. , Patel Dilip D. , Knight Brian L. , Neuwirth Clare K. Y. , Bourbon Mafalda , Soutar Anne K. , Taylor Graham W. , Thompson Gilbert R. , Naoumova Rossitza P.
Published: June 2011

Abstract
—Interindividual variability in low density lipoprotein (LDL) cholesterol (LDL-C) response during treatment with statins is well documented but poorly understood. To investigate potential metabolic and genetic determinants of statin responsiveness, 19 patients with refractory heterozygous familial hypercholesterolemia were sequentially treated with placebo, atorvastatin (10 mg/d), bile acid sequestrant, and the 2 combined, each for 4 weeks. Levels of LDL-C, mevalonic acid (MVA), 7-α-OH-4-cholesten-3-one, and leukocyte LDL receptor and hydroxymethylglutaryl coenzyme A reductase mRNA were determined after each treatment period. Atorvastatin (10 mg/d) reduced LDL-C by an overall mean of 32.5%. Above-average responders (ΔLDL-C −39.5%) had higher basal MVA levels (34.4±6.1 μmol/L) than did below-average responders (ΔLDL-C −23.6%,
P
<0.02; basal MVA 26.3±6.1 μmol/L,
P
<0.01). Fewer good responders compared with the poor responders had an apolipoprotein E4 allele (3 of 11 versus 6 of 8, respectively;
P
<0.05). There were no baseline differences between them in 7-α-OH-4-cholesten-3-one, hydroxymethylglutaryl coenzyme A reductase mRNA, or LDL receptor mRNA, but the latter increased in the good responders on combination therapy (
P
<0.05). Severe mutations were not more common in poor than in good responders. We conclude that poor responders to statins have a low basal rate of cholesterol synthesis that may be secondary to a genetically determined increase in cholesterol absorption, possibly mediated by apolipoprotein E4. If so, statin responsiveness could be enhanced by reducing dietary cholesterol intake or inhibiting absorption.
HMG-CoA Reductase Inhibitors Prevent Migration of Human Coronary Smooth Muscle Cells Through Suppression of Increase in Oxidative Stress
Authors: Yasunari Kenichi , Maeda Kensaku , Minami Mieko , Yoshikawa Junichi
Published: June 2011

Abstract
—In vitro and in vivo evidence of a decrease in vascular smooth muscle cell (SMC) migration induced by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been reported. When added to SMC cultures for 6 hours, the HMG-CoA reductase inhibitors fluvastatin, simvastatin, and pravastatin at 1 μmol/L resulted in a 48%, 50%, and 16% suppression, respectively, of human coronary SMC migration; these reductions mirrored the suppression in oxidative stress induced by 1 μmol/L lysophosphatidylcholine (lyso-PC) of 50%, 53% and 19%, respectively. The hydroxylated metabolites of fluvastatin, M
2
and M
3
, at 1 μmol/L also suppressed the enhancement of SMC migration by 58% and 45% and the increase in oxidative stress induced by lyso-PC of 58% and 49%, respectively. Lyso-PC activated phospholipase D and protein kinase C (PKC), and this activation was also suppressed by HMG-CoA reductase inhibitors. The inhibition of phospholipase D and PKC was reversed by 100 μmol/L mevalonate, its isoprenoid derivative, farnesol, and geranylgeraniol but not by 10 μmol/L squalene. Antisense oligodeoxynucleotides at 5 μmol/L to PKC-α, but not those to the PKC-β isoform, suppressed the lyso-PC–mediated increases in SMC migration and oxidative stress. These findings suggest that HMG-CoA reductase inhibitors have direct antimigratory effects on the vascular wall beyond their effects on plasma lipids and that they might exert such antimigratory effects via suppression of the phospholipase D– and PKC (possibly PKC-α)-induced increase in oxidative stress, which might in turn prevent significant coronary artery disease.
Elevated C-Reactive Protein
Authors: Lemieux Isabelle , Pascot Agnès , Prud’homme Denis , Alméras Natalie , Bogaty Peter , Nadeau André , Bergeron Jean , Després Jean-Pierre
Published: June 2011

Abstract
—Recent studies have suggested that elevated plasma C-reactive protein (CRP) levels are associated with the features of insulin resistance syndrome. In the present study, we have examined the contribution of body composition measured by hydrostatic weighing and of abdominal adipose tissue (AT) accumulation assessed by computed tomography to the variation in plasma CRP levels associated with atherogenic dyslipidemia of the insulin resistance syndrome in a sample of 159 men, aged 22 to 63 years, covering a wide range of adiposity (body mass index values from 21 to 41 kg/m
2
). Plasma CRP levels showed positive and significant correlations with body fat mass (
r
=0.41,
P
<0.0001), waist girth (
r
=0.37,
P
<0.0001), and visceral AT accumulation measured by computed tomography at L4 to L5 (
r
=0.28,
P
<0.0003). Although CRP levels were associated with plasma insulin levels measured in the fasting state and after a 75-g oral glucose load, no significant correlations were found with plasma lipoprotein levels. Finally, comparison of body fatness, of abdominal fat accumulation, and of the features of the insulin resistance syndrome across quintiles of CRP revealed major differences in body fatness and in indices of abdominal AT accumulation between the lowest and the highest CRP quintiles, whereas no significant differences were found for variables of the plasma lipoprotein-lipid profile. These results suggest that obesity and abdominal AT accumulation are the critical correlates of elevated plasma CRP levels found in men with atherogenic dyslipidemia of the insulin resistance syndrome.
Energy Restriction and Weight Loss on Very-Low-Fat Diets Reduce C-Reactive Protein Concentrations in Obese, Healthy Women
Authors: Heilbronn L. K. , Noakes M. , Clifton P. M.
Published: June 2011

Abstract
—C-reactive protein (CRP) is an inflammatory-response protein that is a strong, independent predictor of cardiovascular mortality. CRP is positively associated with body mass index (BMI). In this study, we investigated the effects of dynamic weight loss on CRP in 83 healthy, obese women (mean BMI, 33.8±0.4 kg/m
2
; range, 28.2 to 43.8 kg/m
2
). Subjects were placed on very-low-fat, energy-restricted diets (5700 kJ, 15% fat) for 12 weeks. Weight, waist and hip circumferences, plasma lipids, glucose, and CRP were measured at baseline and after 12 weeks. CRP was positively associated with BMI (
r
=0.281,
P
=0.01) and waist circumference (
r
=0.278,
P
=0.01) but was not related to other atherosclerosis risk factors. BMI was significantly different between groups split above or below the median for CRP (34.8±0.6 kg/m
2
vs 33.0±0.5 kg/m
2
,
P
=0.02). After 12 weeks, weight loss was 7.9±0.3 kg. CRP was significantly decreased by 26% (
P
<0.001), and a correlation was observed between weight loss and the change in CRP (
r
=0.309,
P
=0.005). The variance in the change in CRP was partly explained by initial CRP (13.6%), energy intake (5.4%), and percentage weight loss (4.6%,
P
=0.001). This study confirms recent observations that BMI is associated with CRP, a marker for low-grade systemic inflammation. Furthermore, we observed that CRP was lowered in proportion to weight loss.
Point Mutation (−69 G→A) in the Promoter Region of Cholesteryl Ester Transfer Protein Gene in Japanese Hyperalphalipoproteinemic Subjects
Authors: Nagano Makoto , Yamashita Shizuya , Hirano Ken-ichi , Kujiraoka Takeshi , Ito Mayumi , Sagehashi Yukiko , Hattori Hiroaki , Nakajima Norimichi , Maruyama Takao , Sakai Naohiko , Egashira Tohru , Matsuzawa Yuji
Published: June 2011

Abstract
—Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) from HDL to apolipoprotein (apo) B–containing lipoproteins and plays a crucial role in reverse cholesterol transport, which is a major protective system against atherosclerosis. Genetic CETP deficiency is the most common cause of a marked hyperalphalipoproteinemia (HALP) in the Japanese, and various mutations have been identified in the coding region as well as in the exon/intron boundaries in the CETP gene. In the present study, we identified a novel mutation in the promoter region of the CETP gene. This mutation was a G-to-A substitution at the −69 nucleotide of the promoter region (−69 G→A), corresponding to the second nucleotide of the PEA3/ETS binding site (C
G
GAA) located upstream of the putative TATA box. Four (2.0%) of 196 unrelated subjects with a marked HALP (HDL cholesterol ≥2.59 mmol/L=100 mg/dL) were revealed to be heterozygous for the −69 G→A mutation, and the allelic frequency of the mutant was 0.0102 in the subjects with a marked HALP. The subjects with the −69 G→A mutation had low plasma CETP levels. Reporter gene assay showed that this mutation markedly reduced the transcriptional activities in HepG2 cells (8% of wild type). These results suggested that this mutation would be dominant negative. In conclusion, a novel −69 G→A mutation in the CETP gene causes the decreased transcriptional activity leading to HALP.
Risk factors for peripheral atherosclerosis. Retrospective evaluation by stepwise discriminant analysis.
Authors: Pilger E , Pristautz H , Pfeiffer K P , Kostner G
Published: June 2011

To evaluate the optimal discriminators for peripheral atherosclerosis, we studied retrospectively 49 male patients and 39 male controls between 40 and 60 years of age. In addition to hypertension, cigarette smoking, diabetes mellitus, and hyperuricemia, we determined the most common lipids, lipoproteins, and apolipoproteins. Highly significant differences of median values between patients and controls in decreasing order of magnitude were recorded for apo A-II/apo B, apo A-I/apo B, apo B, total cholesterol, and LDL-cholesterol. A retrospective classification of patients and controls under optimal conditions with one variable (apo A-I/apo B) yielded an error rate of 25%. We found that apolipoproteins were better discriminators for peripheral atherosclerosis than than were lipids or lipoprotein lipids. The application of a linear regression discriminant analysis including 29 variables greatly decreased the rate of error and increased the sensitivity and specificity of the classification. From 229 possible models, we used an economic selection strategy to sort out those which either gave the best segregation or were considered the most practicable. The optimal model with 14 variables gave an error rate of less than 5% for the group studied. Suboptimal models yielded error rates between 13% and 18%. We conclude that a mathematical treatment of laboratory data which includes lipid parameters in addition to apolipoprotein values can improve the classification of peripheral vascular atherosclerosis.
Enhanced cholesterol delivery to cells in culture by low density lipoproteins from hypercholesterolemic monkeys.
Authors: St Clair R W , Greenspan P , Leight M
Published: June 2011

Previous studies have shown that the large molecular weight low density lipoprotein (LDL) of abnormal composition isolated from hypercholesterolemic nonhuman primates stimulates greater cholesterol accumulation in cells in culture than does the same amount of normal LDL. The purpose of the present study was to determine if a correlation existed over a range of LDL molecular weights with cholesterol accumulation in cells in culture, if the differential in cholesterol accumulation was the result of increased delivery of cholesterol to the cells and to evaluate the extent to which this differential was dependent on a functional LDL receptor pathway. Monkey and human skin fibroblasts were incubated for 24 hours with LDL isolated from individual normal or hypercholesterolemic cynomolgus monkeys having LDL molecular weights ranging from 2.58-6.39 x 10(6), and the cellular free and esterified cholesterol contents were determined. There was no correlation of LDL molecular weight with accumulation of cellular free or esterified cholesterol with LDL from normal animals having molecular weight of 2.58 to 3.08 X 10(6) or from hypercholesterolemic animals with LDL molecular weights greater than 4.5 x 10(6). There was a positive and significant correlation of LDL molecular weight with the accumulation of cellular free and esterified cholesterol with LDL molecular weights of 3.0 x 4.5 x 10(6). These differences were present when the LDL were added at equivalent protein or cholesterol concentrations and cannot be entirely explained by the increased amounts of cholesterol in LDL particles of larger molecular weight. The enhanced cellular cholesterol accumulation with hypercholesterolemic LDL seems to be the result of increased delivery of LDL cholesterol to the cells as shown by the increased rate of suppression of cellular sterol synthesis and LDL receptor activity, the increased stimulation of cholesterol esterification, and the increased accumulation of cellular 3H-cholesterol from LDL labeled with 3H-cholesteryl oleate. This difference in cellular cholesterol accumulation requires that the LDL must be both bound and internalized by a functional LDL receptor pathway, since cells that lack LDL receptors or are unable to internalize their LDL receptors do not show increased accumulation of cholesterol when incubated with hypercholesterolemic LDL.
Hyperlipidemia in the Pacific Northwest Bell Telephone Company Health Survey. Part 2. Lipoprotein lipid interrelationships.
Authors: Walden C E , Knopp R H , Wahl P W , Hoover J J , Albers J J , Hazzard W R , Ogilvie J T , Warnick G R
Published: June 2011

The relationships of lipoprotein cholesterol and triglyceride among lipoprotein fractions have potential significance for understanding atherogenesis and distinguishing among different classes of hyperlipidemia. We have compared these relationships in normolipidemic, hypercholesterolemic, hypertriglyceridemic, and combined hyperlipidemic participants in the Pacific Northwest Bell Telephone Company Health Survey. The cholesterol/triglyceride ratio in each lipoprotein fraction was moderately higher (1% to 26%) in hypercholesterolemia but significantly lower (20% to 50%) in hypertriglyceridemia, compared to normolipidemia. In combined hyperlipidemia, the very low density lipoprotein ratios were lower than in normolipidemia, but larger than in hypertriglyceridemia. These changes were directionally the same, but differed quantitatively, in both men and women. Correlation coefficients between cholesterol and triglyceride within each fraction varied by gender and sex hormone use. The largest correlations were seen in combined hyperlipidemic men for very low density lipoproteins, normolipidemic men for low density lipoproteins, and combined hyperlipidemic women taking hormones for high density lipoproteins. The correlation of very low and low density lipoprotein cholesterol was generally negative and was strongest for hormone users (r = -0.81) and weakest for nonusers (r = -0.06). Very low density lipoprotein triglyceride and high density lipoprotein cholesterol correlations were generally negative and were strongest in hypertriglyceridemic women not taking hormones (r = -0.55) and weakest in normolipidemic hormone users (r = -0.10). This correlation was positive for hypertriglyceridemic and combined hyperlipidemic hormone users.
Influence of exercise and life-style variables upon high density lipoprotein cholesterol after myocardial infarction.
Authors: Kavanagh T , Shephard R J , Lindley L J , Pieper M
Published: June 2011

Two groups of postcoronary patients (n = 35 and n = 27) were followed for 1 year. Group 1, recruited 2 to 3 months after infarction, showed a 9% gain of maximum oxygen intake in response to an average of 878 km of walking at speeds increasing to 6.9 km.hr-1. High density lipoprotein (HDL) cholesterol showed a statistically significant, but small, increase over the period of training. If expressed as a ratio to either low density lipoprotein or total cholesterol, the change was correlated with decreases of cigarette consumption, alcohol intake, and body mass, but was unrelated to speed or training distance. Group 2 patients trained an average of 50 to 80 km a week. In this group, HDL cholesterol correlated well with the weekly running distance, declining in those subjects who detrained, and increasing in those who intensified their training. We conclude that the dose of exercise necessary for inducing any substantial increase of HDL cholesterol is about 20 km.wk-1.
Apolipoprotein E polymorphism and coronary artery disease.
Authors: Menzel H J , Kladetzky R G , Assmann G
Published: June 2011

Lipid status and apolipoprotein E phenotypes were tested in 1000 patients who underwent coronary angiography. The same number of factory employees was chosen as a control group. We distinguished between six different apolipoprotein E phenotypes and determined their frequencies in all groups. For the three homozygous phenotypes E3/3, E4/4, and E2/2, the percentage distribution in the group of factory employees was 62.7%, 2.3%, and 0.8%, respectively; for the three heterozygous phenotypes E4/3, E3/2, and E4/2, we determined frequencies of 20.3%, 11.0%, and 3.0%, respectively. In the group of patients with and without signs of coronary atherosclerosis, we observed almost the same frequencies except that heterozygotes (E3/2) occurred significantly more frequently in the group of coronary angiography patients unaffected by coronary sclerosis. Cholesterol and triglyceride values were significantly elevated in patients with coronary artery disease, whereas high density lipoprotein cholesterol levels were not significantly different. The data further suggest that apolipoprotein E2/2 homozygosity, despite the presence of beta-very low density lipoproteins in the plasma of these patients, cannot be considered a biochemical indicator of an increased risk of coronary atherosclerosis. On the other hand, apolipoprotein E3/2 heterozygosity may have a protective effect on the development of early atherosclerosis.
Serum triglyceride and risk of coronary heart disease, stroke, and total mortality in Japanese-American men.
Authors: Rhoads G G , Feinleib M
Published: June 2011

The role of serum triglyceride as a risk factor for coronary heart disease (CHD), stroke, and total mortality was examined in men of Japanese ancestry who were 45 to 78 years old. During the first 10 years following a baseline nonfasting triglyceride determination, there were 490 incidence cases of CHD in 7615 men at risk. Average annual incidence rates were 2.1 times higher in men with nonfasting values above the 75th percentile (279 mg/dl) than in those under the 25th percentile (129 mg/dl, p less than 0.001). This association largely disappeared when associations of triglyceride with other CHD risk factors were accounted for. Fasting triglycerides were measured in a representative sample of 1729 men part-way through the study. With an average follow-up of 5.7 years there were 72 new CHD cases in this group with the risk for men in the top quartile (above 195 mg/dl) being 1.9 times higher than for those in the bottom quartile (below 94 mg/dl). This gradient was of borderline significance (p less than 0.10) and completely disappeared in a multivariate analysis which included HDL and other factors. It appears that the association of triglyceride with CHD in this cohort is of a noncausal nature. Triglycerides were not predictive of stroke or of total mortality in these men.
Variability in individual serum cholesterol response to change in diet.
Authors: Jacobs D R , Anderson J T , Hannan P , Keys A , Blackburn H
Published: June 2011

Few systematic data are available on the range of individual blood lipid responsiveness to specific diet changes. Multiple, carefully standardized total serum cholesterol (TC) measurements were made in 58 men under a variety of controlled dietary conditions. Responsiveness was defined for each individual as the change in mean TC per unit change in Diet Score based on the Keys-Minnesota equation. Only 3% were potentially "nonresponders," and even these probably evidenced some response. Of the group, 64% responded within 30% of prediction. We classed 9% as hyporesponders, while in another 9% responsiveness exceeded 1.5 times expectation. We conclude that in metabolically normal individuals the variation in short-term response to dietary change is normally distributed but that nonresponse to diet change is rare. Because metabolic, intrinsic hyporesponsiveness of TC to change in diet composition is uncommon, assessment of the real effectiveness of a dietary regimen in an individual is best based on observed dietary changes. TC changes among individuals under treatment should be based on multiple determinations and interpreted with caution.
Combined therapy of niacin, colestipol, and fat-controlled diet in men with coronary bypass. Effect on blood lipids and apolipoproteins.
Authors: Nessim S A , Chin H P , Alaupovic P , Blankenhorn D H
Published: June 2011

The effects of colestipol (30 grams/day), niacin (7.3 grams/day), and diet on blood lipids and apolipoproteins after one year of therapy are reported. Men selected on the basis of previous coronary artery bypass surgery were randomly assigned to drug or control treatments in an angiographic study of atherosclerosis progression and regression. In 14 men, drugs and diet produced the following changes: Baseline total cholesterol 245 mg/dl, triglyceride 189 mg/dl, and LDL cholesterol 164 mg/dl were decreased by 73 mg/dl (29%), 83 mg/dl (41%) and 69 mg/dl (40%) respectively. Baseline HDL cholesterol, 44 mg/dl was increased 13 mg/dl (33%). Baseline apolipoprotein B, 124 mg/dl and apolipoprotein C-III (heparin precipitate) 5.6 mg/dl were decreased 40 mg/dl (31%) and 2.4 mg/dl (41%) respectively. All these changes are significant, p less than 0.01. Apolipoprotein A-I and apolipoprotein C-III (heparin supernate) were not significantly changed. In the controls, placebo and diet produced no significant decrease in blood lipid or lipoproteins, with the exception that baseline apolipoprotein B, 111 mg/dl increased 18 mg/dl (12%), p less than 0.05.
Cholesterol-induced atherosclerosis. Clonal characteristics of arterial lesions in the hybrid hare.
Authors: Pearson T A , Dillman J , Malmros H , Sternby N , Heptinstall R H
Published: June 2011

Utilizing the observation that a majority of human atherosclerotic fibrous plaques show monoclonal characteristics, we carried out this study to determine the clonal characteristics of cholesterol-induced atherosclerosis in the hybrid hare. If this is a valid model for human atherosclerosis, the lesions produced in the aorta should be monoclonal. Glucose-6-phosphate dehydrogenase (G-6-PD) was used as an X-linked cellular marker in the female hybrid hare (Lepus timidus X Lepus europaeus), which is heterozygous for electrophoretically separable isoenzymes of G-6-PD. Hares were fed cholesterol over either a 6-month or a 16-month period, and the easily dissectable lesions in the aorta and common iliac arteries were assayed for isoenzyme activity at these times. Of the 93 lesions assayed, all had polyclonal characteristics except a single monoclonal lesion found in an animal fed cholesterol over a 16-month period. Hares fed over the 16-month period showed lesions with isoenzyme patterns having a significantly higher contribution of L. timidus isoenzyme than those found in underlying media. This suggested that a selection of cells with the L. timidus X-chromosome had taken place, but the degree of this selection was not great enough to allow any of the lesions to be defined as monoclonal.
Angiotensin-converting enzyme in cultured endothelial cells. Synthesis, degradation, and transfer to culture medium.
Authors: Ching S F , Hayes L W , Slakey L L
Published: June 2011

Cultured endothelial cells from swine aorta possess the ecto-enzyme angiotensin-converting enzyme (E.C.3.4.15.1) in cell-associated form and also release it in soluble form into the culture medium. Using antibody to purified converting enzyme from swine kidney and incorporation of 3H-leucine, we examined the synthesis, degradation, and release of enzyme into the medium. 3H-leucine is incorporated into cellular converting enzyme, and later appears in the enzyme in the culture medium. The amount of cell-associated enzyme activity remains constant, and the amount of activity in the medium increases linearly during this period. These data show unequivocally that the appearance of enzyme activity in the cell culture medium is accompanied by synthesis of new enzyme protein. In pulse-chase experiments, the radioactivity disappeared from the cellular enzyme in two kinetic components with apparent half-lives of 1-2 hours and 20 hours, respectively. The appearance of the radiolabel in the medium enzyme corresponds very closely in rate and amount to the slow disappearance from the cells. There was no apparent uptake of labeled medium enzyme by the cells. The data suggest that the pool of active enzyme on the cell surface is the immediate precursor of the medium enzyme. The effects of culture conditions on the turnover of angiotensin-converting enzyme were also examined. The incorporation of 3H-leucine into both cell and medium enzyme was greater when cells were maintained in medium containing serum than when they were maintained in serum-free medium. The rate of degradation of the cellular enzyme was similar under the two culture conditions.
Aortic endothelial and smooth muscle histamine metabolism. Relationship to aortic 125I-albumin accumulation in experimental diabetes.
Authors: Hollis T M , Gallik S G , Orlidge A , Yost J C
Published: June 2011

We studied rat aortic endothelial and smooth muscle cell de novo histamine synthesis mediated by histidine decarboxylase (HD) and the effects of its inhibition by alpha-hydrazinohistidine on the intracellular histamine content and intraaortic albumin accumulation in streptozotocin-induced diabetes. Diabetes was induced by a single jugular vein injection of streptozotocin (60 mg/kg, pH 4.5, ether anesthesia), with animals held 4 weeks following the overt manifestation of diabetes. Additional diabetic and nondiabetic rats received alpha-hydrazinohistidine (25 mg/kg, i.p. every 12 hours) during the last week; this had no effect on the severity of diabetes in any animal receiving streptozotocin. Data indicate that the aortic endothelial (EC) HD activity was increased more than 130% in the untreated diabetic group but was similar to control values in the diabetic group receiving alpha-hydrazinohistidine; similarily, the EC histamine content from diabetic aortas increased 127% over control values, but in EC from diabetic animals receiving alpha-hydrazinohistidine it was comparable to control values. Similar trends were observed for the subjacent aortic smooth muscle. In untreated diabetic animals the aortic 125I-albumin mass transfer rate was increased 60% over control values, while in diabetic animals receiving alpha-hydrazinohistidine the 125I-albumin mass transfer rate was essentially identical to controls. These data indicate that in streptozotocin diabetes there is an expansion of the inducible aortic histamine pool, and that this expansion is intimately related to the increased aortic albumin accumulation.