bluuebunny/crossref_metadata_2025 huggingface dataset:
NAD(P)H Oxidase Mediates Angiotensin II–Induced Vascular Macrophage Infiltration and Medial Hypertrophy
Authors: Liu Jianhua , Yang Fang , Yang Xiao-Ping , Jankowski Michelle , Pagano Patrick J.
Published: May 2003

Objective—Our preliminary data suggested that angiotensin II (Ang II)–induced reactive oxygen species are involved in intercellular adhesion molecule-1 (ICAM-1) expression and leukocyte infiltration in the rat thoracic aorta. Other reports demonstrating reactive oxygen species–induced cell growth suggested a potential role of NAD(P)H oxidase in vascular hypertrophy. In the present study, we postulate that NAD(P)H oxidase is functionally involved in Ang II–induced ICAM-1 expression, macrophage infiltration, and vascular growth, and that oxidase inhibition attenuates these processes independently of a reduction in blood pressure.

Methods and Results—Rats were infused subcutaneously with vehicle or Ang II (750 μg/kg per day) for 1 week in the presence or absence of gp91 docking sequence (gp91ds)-tat peptide (1 mg/kg per day), a cell-permeant inhibitor of NAD(P)H oxidase. Immunohistochemical staining for ICAM-1 and ED1, a marker of monocytes and macrophages, showed that both were markedly increased with Ang II compared with vehicle and were reduced in rats receiving Ang II plus gp91ds-tat. This effect was accompanied by an Ang II–induced increase in medial hypertrophy that was attenuated by coinfusion of gp91ds-tat; however, gp91ds-tat had no effect on blood pressure.

Conclusions—Ang II–enhanced NAD(P)H oxidase plays a role in the induction of ICAM-1 expression, leukocyte infiltration, and vascular hypertrophy, acting independently of changes in blood pressure.
LOX-1, an Oxidized LDL Endothelial Receptor, Induces CD40/CD40L Signaling in Human Coronary Artery Endothelial Cells
Authors: Li Dayuan , Liu Ling , Chen Hongjiang , Sawamura Tatsuya , Mehta Jawahar L.
Published: May 2003

Background—

Despite increasing appreciation that atherogenesis involves participation of inflammatory cells, information on mediators of communication between different constituents of atherosclerotic plaque remain incomplete. We examined the role of LOX-1, a receptor for oxidized (ox) LDL, in the expression of CD40/CD40L in cultured human coronary artery endothelial cells (HCAECs).

Methods and Results—

We observed that ox-LDL increased the expression of CD40 and CD40L in a concentration (10 to 80 μg/mL)- and time (1 to 24 hours)- dependent manner. These effects of ox-LDL were mediated by activation of LOX-1, because pretreatment of HCAECs with a blocking antibody to LOX-1 (JTX92) prevented the expression of CD40 and CD40L in response to ox-LDL (
P
<0.01). In parallel experiments, HCAECs were incubated with the protein kinase C (PKC) inhibitor bisindolylmaleimide I, and the cells were then exposed to ox-LDL. Both LOX-1 antibody and the PKC inhibitor inhibited PKC activation in response to ox-LDL (
P
<0.01). The PKC inhibitor also blocked the effects of ox-LDL on the expression of CD40 and CD40L (
P
<0.01). In additional experiments, we found that it is the PKCα, but not PKCβ and PKCγ, isoform that mediated ox-LDL–induced CD40 and CD40L upregulation. Further experiments showed that upregulation of CD40 mediated induction of proinflammatory genes, because CD40 antibody markedly reduced ox-LDL–induced TNF-α generation and P-selectin expression, whereas nonspecific mouse IgG had no effect.

Conclusions—

These findings indicate that ox-LDL through its receptor LOX-1 triggers the CD40/CD40L signaling pathway that activates the inflammatory reaction in HCAECs. These observations provide novel insight into ox-LDL–mediated inflammation in atherosclerosis.
Structure, Function, and Endothelium-Derived Hyperpolarizing Factor in the Caudal Artery of the SHR and WKY Rat
Authors: Sandow Shaun L. , Bramich Narelle J. , Bandi Hari Priya , Rummery Nicole M. , Hill Caryl E.
Published: May 2003

Objective—

To quantify structural and functional characteristics of the caudal artery from spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats with particular reference to endothelium-derived hyperpolarizing factor (EDHF).

Methods and Results—

Ultrastructural studies showed that the number of myoendothelial gap junctions, smooth muscle cell (SMC) layers, and medial cross-sectional area were significantly greater in SHR than WKY. Intracellular dye labeling demonstrated hyperplasia of SMCs in SHR. Analysis of nerve-mediated excitatory junction potentials recorded in SMCs at the adventitial and luminal borders demonstrated decreased radial coupling of SMCs in SHR. In both SHR and WKY, in the presence of
N
G
-nitro-
l
-arginine methyl ester and indomethacin, acetylcholine-elicited EDHF was abolished by charybdotoxin and apamin, while iberiotoxin had no effect, implicating the involvement of small and intermediate, but not large, calcium-activated potassium channels. EDHF was abolished by Gap-mimetic peptides, 18β-glycyrrhetinic acid, and endothelial removal but not affected by the NO scavengers hydroxocobalamin and carboxy-PTIO.

Conclusions—

Significant differences in SMC morphology and homocellular and heterocellular coupling exist between the caudal artery of SHR and WKY rats. In the caudal artery of SHR, significantly greater heterocellular coupling compensates for other structural changes in the media to maintain a functional role for EDHF.
White Cell Telomere Length and Risk of Premature Myocardial Infarction
Authors: Brouilette Scott , Singh Ravi K. , Thompson John R. , Goodall Alison H. , Samani Nilesh J.
Published: May 2003

Objective—

Biological age may be distinct from chronological age and contribute to the pathogenesis of age-related diseases. Mean telomeres lengths provide an assessment of biological age with shorter telomeres, indicating increased biological age. We investigated whether subjects with premature myocardial infarction (MI) had shorter leukocyte telomeres.

Methods and Results—

Mean terminal restriction fragment (TRF) length, a measure of average telomere size, was compared in leukocyte DNA of 203 cases with a premature MI (<50 years) and 180 controls. Age- and sex-adjusted mean TRF length of cases was significantly shorter than that of controls (difference 299.7±69.3 base pairs,
P
<0.0001) and on average equivalent to controls 11.3 years older. The difference in mean TRF length between cases and controls was not accounted for by other coronary risk factors. Compared with subjects in the highest quartile for telomere length, the risk of myocardial infarction was increased between 2.8- and 3.2-fold (
P
<0.0001) in subjects with shorter than average telomeres.

Conclusions—

The findings support the concept that biological age may play a role in the etiology of coronary heart disease and have potentially important implications for our understanding of its genetic etiology, pathogenesis, and variable age of onset.
E-Selectin Polymorphism Associated With Myocardial Infarction Causes Enhanced Leukocyte-Endothelial Interactions Under Flow Conditions
Authors: Yoshida Masayuki , Takano Yoshio , Sasaoka Taishi , Izumi Toru , Kimura Akinori
Published: May 2003

Objective—Polymorphisms found in genes encoding adhesion molecules have been reported to be associated with atherosclerosis. We investigated the Ser128Arg polymorphism in the E-selectin gene in Japanese patients with myocardial infarction and its functional significance.

Methods and Results—Results from 135 patients with myocardial infarction and 327 control subjects revealed that the frequency of Arg128-positive was significantly higher in the patients than in controls (12.6% versus 6.7%; odds ratio, 2.0; 95% CI, 1.04 to 3.85), indicating that the Ser128Arg polymorphism was associated with myocardial infarction. We then generated a recombinant E-selectin adenovirus carrying a mutation (AdS128R-E) and compared it with its wild-type counterpart by evaluating the adhesion characteristics of transduced human umbilical vein endothelial cells under flow. AdS128R-E–transduced human umbilical vein endothelial cells supported significantly more rolling and adhesion of neutrophils and mononuclear cells compared with human umbilical vein endothelial cells transduced with AdWT-E (P<0.001) and also exhibited significantly greater levels of phosphorylation of extracellular signal regulated kinase 1 and 2 and p38 mitogen-activated protein kinase, suggesting that an altered endothelial signaling pathway is associated with this polymorphism.

Conclusions—Our results suggest that the E-selectin Ser128Arg polymorphism can functionally alter leukocyte-endothelial interactions as well as biochemical and biological consequences, which may account for the pathogenesis of myocardial infarction.
Arterial Remodeling and Stiffness in Patients With Pseudoxanthoma Elasticum
Authors: Germain Dominique P. , Boutouyrie Pierre , Laloux Brigitte , Laurent Stéphane
Published: May 2003

Objective—

Proteoglycans organize the extracellular matrix, act as signaling molecules, and are involved in cell migration and proliferation. They may play an important role in arterial geometric and elastic properties. The aim of the present study was to determine large artery phenotype in patients with pseudoxanthoma elasticum (PXE), a genetic disease characterized by proteoglycan accumulation and fragmented elastic fibers in connective tissues.

Methods and Results—

In 27 patients with PXE (25 females and 2 male) and 27 control subjects matched by age, sex, and blood pressure, we noninvasively determined the common carotid and radial artery diameter, intima-media thickness (IMT), and distensibility with high-definition echo-tracking systems and applanation tonometry. Patients with PXE had a significantly higher carotid IMT (611±106 versus 520±76 μm,
P
<0.001) independently of body surface area, age, and mean blood pressure. The increase in carotid IMT predominated in older patients with PXE at the time of examination. No significant difference in carotid elastic properties was observed between patients with PXE and control subjects. At the site of the radial artery, distensibility was significantly higher in patients with PXE than in control subjects (11.6±11.4 versus 5.9±3.4 kPa
−1
· 0.10
−3
;
P
=0.02) and internal diameter was lower (1.66±0.51 versus 2.07±0.36 mm;
P
<0.01) without change in intima-media thickness and Young’s elastic modulus.

Conclusions—

Phenotypic changes of superficial arteries in patients with PXE were represented by a thickening of the carotid artery and a reduced stiffness of the radial artery and predominated in older female patients.
Expression of Human Scavenger Receptor B1 on and in Human Platelets
Authors: Imachi Hitomi , Murao Koji , Cao Wenming , Tada Satoshi , Taminato Tomohiko , Wong Norman C.W. , Takahara Jiro , Ishida Toshihiko
Published: May 2003

Objective—The abundance of HDL particles correlates inversely with the incidence of coronary heart disease. The human scavenger receptor B1 (hSR-B1/CLA-1) is a receptor for HDL. Expression of hSR-B1/CLA-1 mRNA and protein in human platelets was determined using reverse transcriptase–polymerase chain reaction and Western blot, respectively. Presence of the protein on the surface of platelets was shown using flow cytometry.

Methods and Results—Immunochemical staining for hSR-B1/CLA-1 showed that it was expressed in megakaryocytes, the platelet precursors of human bone marrow. These findings prompted us to ask whether hSR-B1/CLA-1 was differentially expressed on platelets obtained from patients with atherosclerotic disease compared with those in control subjects. Our findings showed that abundance of hSR-B1/CLA-1 was significantly reduced on the surface of platelets from patients with atherosclerotic disease. The reduced levels of hSR-B1/CLA-1 were associated with increased cholesterol ester content in platelets from patients with atherosclerotic disease compared with control subjects. A negative correlation existed between hSR-B1/CLA-1 expression and platelet aggregation. In summary, our studies show that the HDL receptor hSR-B1/CLA-1 is expressed in platelets and their precursor, the megakaryocyte. The levels of hSR-B1/CLA-1 expression correlate inversely with cholesterol ester content and platelet aggregation.

Conclusion—These findings suggest that determining the level of hSR-B1/CLA-1 expression on the platelets may be a useful clinical marker for atherosclerotic diseases.
Soluble Tissue Factor Induces Coagulation on Tumor Endothelial Cells In Vivo if Coadministered With Low-Dose Lipopolysaccharides
Authors: Philipp Jana , Dienst Ariane , Unruh Maike , Wagener Anke , Grunow Andrea , Engert Andreas , Fries Jochen W.U. , Gottstein Claudia
Published: May 2003

Objective—

This study was performed to evaluate the mechanisms leading to tumor vessel occlusion by tissue factor–based drugs, which are used in vascular targeting approaches for the treatment of malignant tumors.

Methods and Results—

The effects of nontargeted soluble tissue factor were evaluated in vitro and in vivo. Tumor-bearing mice were treated with (1) the extracellular portion of tissue factor (soluble tissue factor), (2) low nontoxic doses of lipopolysaccharides, or (3) a combination thereof. The combination treatment showed the best effects and resulted in selective thrombosis of tumor vessels. On the basis of our data from subsequent in vitro analyses, including surface plasmon resonance measurements and endothelial cell based coagulation assays, we propose a model on how soluble tissue factor, although lacking its membrane anchor, can promote selective tumor vessel occlusion.

Conclusions—

To our knowledge, this is the first report to describe the molecular mechanisms of coagulation induction by untargeted soluble tissue factor in vivo. Combination treatments including soluble tissue factor might represent an alternative vascular targeting approach for the treatment of malignant tumors.
Human Plasma Platelet-Activating Factor Acetylhydrolase Binds to All the Murine Lipoproteins, Conferring Protection Against Oxidative Stress
Authors: Noto Hiroshi , Hara Masumi , Karasawa Ken , Iso-O Naoyuki , Satoh Hiroaki , Togo Masako , Hashimoto Yoshiaki , Yamada Yoshiji , Kosaka Tetsuya , Kawamura Mitsunobu , Kimura Satoshi , Tsukamoto Kazuhisa
Published: May 2003

Objective—

Plasma platelet-activating factor (PAF) acetylhydrolase (AH) is an enzyme bound with lipoproteins that degrades not only PAF but also PAF-like oxidized phospholipids that are proposed to promote atherosclerosis. In this study, we investigated the distribution of PAF-AH protein among lipoprotein classes by using adenovirus-mediated gene transfer in mice, and we examined its effects on lipoprotein oxidation and foam cell formation of macrophages.

Methods and Results—

Adenovirus-mediated overexpression of PAF-AH in mice resulted in a 76- to 140-fold increase in plasma PAF-AH activity. Contrary to the previous report, overexpressed human PAF-AH protein was bound to very low density lipoprotein, intermediate density lipoprotein, low density lipoprotein, and high density lipoprotein (HDL). All the lipoproteins with overexpressed human PAF-AH revealed more resistance against oxidative stress, which was associated with lower levels in autoantibody against oxidized low density lipoprotein in the plasma. In addition, HDL with human PAF-AH inhibited foam cell formation and facilitated cholesterol efflux in macrophages.

Conclusions—

These results suggest that human plasma PAF-AH exerts an antiatherogenic effect by binding to all the lipoproteins and thereby protecting them from oxidation, producing less proatherogenic lipoproteins and preserving HDL functions.
Increased Fecal Bile Acid Excretion in Transgenic Mice With Elevated Expression of Human Phospholipid Transfer Protein
Authors: Post Sabine M. , de Crom Rini , van Haperen Rien , van Tol Arie , Princen Hans M.G.
Published: May 2003

Objective—HDL plays a key role in protection against development of atherosclerosis by promoting reverse cholesterol transport from peripheral tissues to the liver for secretion into bile. Phospholipid transfer protein (PLTP) promotes the transfer of phospholipids between lipoproteins and modulates HDL size and composition, thereby having a crucial role in HDL metabolism. We investigated the effect of increased PLTP activity on removal of cholesterol from the body.

Methods and Results—On a chow diet, transgenic mice overexpressing human PLTP have a 15-fold increased plasma PLTP activity compared with wild-type mice (572.4±59.2 versus 38.6±3.6 μmol/mL per h). Plasma cholesterol, mainly present in HDL, is strongly decreased (−92%), caused by a rapid clearance from the circulation by the liver and leading to a 1.8-fold increase in hepatic cholesteryl esters. This results in a 2-fold increase in biliary bile acid secretion without changing the bile saturation index. Consequently, the transgenic mice show a 1.4-fold increase in the amount of excreted fecal bile acids compared with wild-type mice, whereas fecal neutral sterol excretion is unchanged.

Conclusions—Our data show that elevation of PLTP activity results in rapid disposal of cholesterol from the body via increased conversion into bile acids and subsequent excretion.
Effects of Exercise on Cardiovascular Outcomes in Monkeys With Risk Factors for Coronary Heart Disease
Authors: Williams J. Koudy , Kaplan Jay R. , Suparto Irma H. , Fox Jamie L. , Manuck Stephen B.
Published: May 2003

Objective—

Exercise reduces the risk for coronary heart disease. However, the mechanisms mediating the beneficial effects of exercise remain ambiguous. In particular, it is uncertain whether exercise inhibits the development of atherosclerosis, a major pathobiologic process underlying heart disease.

Methods and Results—

To address this question, adult male monkeys were fed an atherogenic diet while assigned to one of four experimental conditions for 34 months: 1) runner/no group disruption, ie, “stable” (n=19); 2) runner plus frequent social group disruption, ie, “unstable” (n=19); 3) sedentary/stable (n=15); or 4) sedentary/unstable (n=18). Neither exposure to exercise nor social group disruption significantly affected the resulting coronary artery atherosclerosis extent or lumen areas (all ANOVA values,
P
>0.05). When compared with sedentary individuals, exercise animals had lower resting heart rates (119.0±3 vs132.0±3 bpm,
P
=0.002), greater echocardiographically measured left ventricular ejection fractions (77.2±0.01% vs 73.8±0.01%,
P
=0.02), greater quantitative angiographically measured dilation of coronary arteries to phenylephrine (2.6±1% vs −3.7±1% change from baseline diameter,
P
=0.003), and a reduced cortisol response to an adrenocorticotropin challenge. These measures were not significantly affected by social condition.

Conclusions—

Thus, exercise improved some measures of cardiovascular health and reduced stress responsivity but did not inhibit progression of coronary artery atherosclerosis or promote positive artery remodeling. It is concluded that exercise may exert cardioprotective effects without influencing atherosclerosis extent.
Identification of Immune Responses Against Aldehyde-Modified Peptide Sequences in ApoB Associated With Cardiovascular Disease
Authors: Fredrikson Gunilla Nordin , Hedblad Bo , Berglund Göran , Alm Ragnar , Ares Mikko , Cercek Bojan , Chyu Kuang-Yuh , Shah Prediman K. , Nilsson Jan
Published: May 2003

Objective—

Atherosclerosis is associated with an immune response against oxidized LDL, which modulates the progression of the disease process.

Methods and Results—

Using a library of polypeptides covering the complete sequence of apoB-100, the only major protein of LDL, we have identified over 100 different human antibodies reacting against aldehyde-modified apoB-100 sequences. IgM antibody titer levels decreased with age and were associated with the intima-media thickness of the carotid artery in subjects younger than 60 years. There were also inverse associations between IgM levels and oxidized LDL in plasma. In prospective clinical studies, antibody levels against several aldehyde-modified apoB-100 sites were associated with cardiovascular disease in this age group. Whether this immune response is adaptive (protective) or maladaptive (causal) in atherosclerosis requires further investigation.

Conclusions—

We have characterized a large number of epitopes within the apoB-100 component of oxidized LDL that provoke an immune response in humans. These findings will make it possible to study the role of immune responses against specific sites in oxidized LDL and to determine whether these immune responses influence the risk for future cardiac events.
Inhibition of Atherosclerosis in ApoE-Null Mice by Immunization with ApoB-100 Peptide Sequences
Authors: Fredrikson Gunilla Nordin , Söderberg Ingrid , Lindholm Marie , Dimayuga Paul , Chyu Kuang-Yuh , Shah Prediman K. , Nilsson Jan
Published: May 2003

Objective—

LDL oxidation is believed to play an important role in the development of atherosclerosis, and oxidized LDL particles have been shown to become targets for the immune system. Immunization of animals with oxidized LDL results in reduction of atherosclerosis, suggesting an atheroprotective effect of this immune response.

Methods and Results—

Using a polypeptide library covering the complete sequence of apoB-100, a large number of native and malondialdehyde-modified peptide sequences in apoB-100 that are recognized by antibodies in human plasma were identified. We report here that immunization with apoB-100 peptide sequences, against which high levels of IgG and IgM antibodies are present in healthy human controls, reduce atherosclerosis in apoE-null mice by about 60%. Immunizations with these peptides were also found to increase the collagen content of subvalvular lesions.

Conclusions—

These studies have identified peptide sequences in apoB-100 that induce immune responses, which inhibits atherosclerosis. This suggests a way of developing an immunization therapy for coronary heart disease.
Recruitment of
Chlamydia pneumoniae
–Infected Macrophages to the Carotid Artery Wall in Noninfected, Nonatherosclerotic Mice
Authors: May Andreas E. , Redecke Vanessa , Grüner Sabine , Schmidt Roland , Massberg Steffen , Miethke Thomas , Ryba Birgit , Prazeres da Costa Clarissa , Schömig Albert , Neumann Franz-Josef
Published: May 2003

Objective—

Monocyte recruitment into the subendothelium is a crucial step in atherogenesis.
Chlamydia pneumoniae
resides in circulating monocytes and in the atherosclerotic vascular wall. However, the role of
C pneumoniae
for monocyte recruitment is unknown. The aim of this study was to examine the impact of
C pneumoniae
on monocyte adhesion and migration.

Methods and Results—

C pneumoniae
–infected, fluorescence-labeled mouse macrophages (ANA-1) were injected intravenously into noninfected, healthy mice. In vivo videomicroscopy showed increased rolling and firm adhesion to the carotid artery compared with noninfected macrophages. In vitro,
C pneumoniae
infection (yielding 25% to 35% infected monocytes) increased adhesion of human monocytes or MonoMac6 cells to human umbilical vein endothelial cells and improved cell migration through endothelial-like ECV604 cells. Cell adhesion was inhibited by antibody blockade of very late antigen-4, lymphocyte function-associated antigen-1, macrophage antigen-1, or urokinase receptor, which were found upregulated or activated on
C pneumoniae
infection (flow cytometry). In contrast,
C trachomatis
did not induce monocyte adhesion at comparable infection rates (25% to 35%), indicating a unique activation pathway for
C pneumoniae
. Polymyxin B did not affect
C pneumoniae
–induced adhesion, excluding a relevant role of lipopolysaccharide in this process.

Conclusions—

These data indicate that
C pneumoniae
can direct monocytes to predilection sites of nonatherosclerotic vessel walls in vivo by activation of the integrin adhesion receptor system.
Statins Inhibit Secretion of Metalloproteinases-1, -2, -3, and -9 From Vascular Smooth Muscle Cells and Macrophages
Authors: Luan Zhaoxia , Chase Alex J. , Newby Andrew C.
Published: May 2003

Objective—Production of several metalloproteinases (MMPs) from smooth muscle cells (SMCs) and macrophages causes matrix destruction and atherosclerotic plaque instability. Statins, which inhibit HMG-CoA reductase and hence cholesterol and isoprenoid synthesis, stabilize plaques. We investigated whether statins inhibit MMP secretion from SMCs and macrophages.

Methods and Results—We used human saphenous vein and rabbit aortic SMC and foamy macrophages from cholesterol-fed rabbits. Cerivastatin (50 nmol/L) inhibited inducible MMP-1, -3, and -9 secretion from human SMC by 52±19%, 71±18%, and 73±17%, respectively (P<0.01, n=3). Similar dose-related effects of cerivastatin (50 to 500 nmol/L), simvastatin (1 to 20 μmol/L), and lovastatin (5 to 20 μmol/L) were consistent with their relative potencies against HMG-CoA reductase. Statins also inhibited inducible MMP-1, -3, and -9 and constitutive MMP-2 secretion but not TIMP-1 or -2 secretion from rabbit SMC. Statins also dose-dependently inhibited MMP-1, -3, and -9 secretion from rabbit foam cells; cerivastatin (50 nmol/L) inhibited by 68±18%, 74±14%, and 74±14%, respectively (P<0.01, n=4). Statins similarly decreased collagenolytic, caseinolytic, and gelatinolytic activity. Mevalonate and geranylgeranylpyrophosphate but not squalene reversed the effects, showing dependence on isoprenoid, not cholesterol depletion. Statins did not affect MMP mRNA levels.

Conclusions—Statins inhibit secretion of a several MMPs from both SMCs and macrophages, which could therefore contribute to their plaque-stabilizing effects.
Alanine for Proline Substitution in the Peroxisome Proliferator–Activated Receptor Gamma-2 (PPARG2) Gene and the Risk of Incident Myocardial Infarction
Authors: Ridker Paul M. , Cook Nancy R. , Cheng Suzanne , Erlich Henry A. , Lindpaintner Klaus , Plutzky Jorge , Zee Robert Y.L.
Published: May 2003

Objective—

Recent studies have implicated the potential importance of peroxisome proliferator–activated receptors as a molecular mechanism involved in atherothrombosis. A common alanine (A) for proline (P) substitution at codon 12 in the peroxisome proliferator activated receptor gamma-2 gene (
PPARG2
) has been associated with reduced risk of developing type 2 diabetes mellitus. Because diabetes and atherothrombosis share common antecedents, we sought evidence that this polymorphism might also be associated with reduced risk of myocardial infarction.

Methods and Results—

Using DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we evaluated a P12A polymorphism in the
PPARG2
among 523 individuals who subsequently developed myocardial infarction and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. As hypothesized, presence of the A12 allele was associated with significantly reduced risk of myocardial infarction (odds ratio in an age- and smoking-adjusted dominant model of inheritance, 0.77; 95% CI, 0.60 to 0.98;
P
=0.034). This protective effect remained statistically significant in analyses controlling for traditional cardiovascular risk factors, was present among nondiabetic study participants, was observed to be of similar magnitude in analyses assuming codominant or dominant modes of inheritance, and was seen in fully adjusted post hoc analyses in which we limited our control group to those individuals specifically matched to myocardial infarction cases (OR, 0.71; 95% CI, 0.53 to 0.96;
P
=0.024).

Conclusions—

In this cohort, a common A for P substitution at codon 12 in the
PPARG2
was associated with reduced incidence of myocardial infarction. If confirmed in other cohorts, these data would have implications for novel treatments of cardiovascular disease, including development of PPARG-targeted therapy.
Lysophosphatidylcholine Regulates Synthesis of Biglycan and the Proteoglycan Form of Macrophage Colony Stimulating Factor
Authors: Chang Mary Y. , Tsoi Christina , Wight Thomas N. , Chait Alan
Published: May 2003

Objective—We have shown that copper-oxidized LDL (Ox-LDL) regulates proteoglycan synthesis by arterial smooth muscle cells. Ox-LDL specifically upregulates biglycan expression while causing elongation of glycosaminoglycan chains on all of the major secreted proteoglycans (biglycan, decorin, and versican), resulting in enhanced lipoprotein-binding interactions. It is not known which component of Ox-LDL is responsible for these effects. This study investigated the ability of several bioactive components of Ox-LDL to regulate proteoglycan synthesis.

Methods and Results—Those tested included 2 oxysterols (7-ketocholesterol and 7β-hydroxycholesterol) and 2 lysolipids (lysophosphatidylcholine and lysophosphatidic acid) formed during LDL oxidation. 7-ketocholesterol, lysophosphatidylcholine, and lysophosphatidic acid all increased proteoglycan MWapp, which is correlated with chain elongation and enhanced lipoprotein-binding properties in vitro. Lysophosphatidylcholine mimics the ability of Ox-LDL to stimulate biglycan expression and also causes a marked induction of the core protein for the proteoglycan form of macrophage colony stimulating factor.

Conclusions—Multiple oxidized lipid molecules can modulate proteoglycan synthesis and may have important consequences to atherogenesis via processes that involve enhanced lipoprotein retention as well as the promotion of macrophage survival and differentiation.
Hypercholesterolemia and Hypertension Have Synergistic Deleterious Effects on Coronary Endothelial Function
Authors: Rodriguez-Porcel Martin , Lerman Lilach O. , Herrmann Joerg , Sawamura Tatsuya , Napoli Claudio , Lerman Amir
Published: May 2003

Objective—

Coronary endothelial dysfunction is associated with an increase in cardiac events. Hypercholesterolemia (HC) and hypertension (HT) are both associated with endothelial dysfunction, and their coexistence is associated with an increased incidence of cardiac events in epidemiological studies. However, pathogenic mechanisms are poorly understood. Here we studied the effects of coexisting HC and HT on coronary endothelial function.

Methods and Results—

Four groups of pigs were studied after 12 weeks of a normal diet (n=9), a 2% HC diet (n=9), HT (achieved by unilateral renal artery stenosis, n=8), or HC+HT (n=6). Coronary endothelial function was tested, in epicardial arteries and arterioles, by using organ chamber techniques. Oxidative stress was measured in coronary artery tissue. Vasodilatory response to bradykinin and calcium ionophore was significantly impaired in animals with HC+HT compared with each risk factor alone (
P
<0.05 for both). In animals with coexistent HC and HT, the increase in oxidative stress was more pronounced compared with each risk factor alone (
P
<0.05). Furthermore, chronic antioxidant supplementation significantly improved coronary artery vasoreactivity.

Conclusions—

These results suggest that HC and HT have a synergistic deleterious effect on coronary endothelial function, associated with increased oxidative stress. This interaction may contribute to the increased incidence of coronary heart disease and cardiac events seen when HC and HT coexist.
Troglitazone Stimulates Repair of the Endothelium and Inhibits Neointimal Formation in Denuded Rat Aorta
Authors: Hannan Katherine M. , Dilley Rodney J. , de Dios Stephanie T. , Little Peter J.
Published: May 2003

Objective—

Vascular endothelium is emerging as a therapeutic target for atherosclerotic macrovascular disease in diabetes using oral hypoglycemic agents with pleiotropic actions. We have addressed whether the thiazolidinedione troglitazone has effects on the endothelial cell response to injury in rat aorta and its interaction with the growth response of underlying vascular smooth muscle.

Methods and Results—

Repair of rat aorta after balloon catheter injury in troglitazone-treated (400 mg/kg per day by mouth) rats showed early acceleration of reendothelialization and late reduction in neointima formation. Complementary in vitro studies showed that troglitazone dose-dependently inhibited migration and proliferation of cultured macrovascular endothelial and vascular smooth muscle cells in low-glucose (5 mmol/L) and high-glucose (25 mmol/L) media. However, in endothelial cells, the inhibitory response at low (<3 μmol/L) troglitazone concentrations resulted from direct inhibition of proliferation, whereas inhibition at higher (10 μmol/L) concentrations was secondary to apoptosis and necrosis. Additional studies indicated a concentration-specific activity of troglitazone to protect endothelial cells from apoptosis.

Conclusions—

Troglitazone had effects consistent with maintenance of vascular integrity and protection against mechanisms of atherosclerosis and restenosis, which may arise from a concentration-specific effect to reduce high rates of apoptosis occurring in cultured cells and repairing vessels.
Fibroblast Growth Factor-2, But Not Vascular Endothelial Growth Factor, Upregulates Telomerase Activity in Human Endothelial Cells
Authors: Kurz David J. , Hong Ying , Trivier Elizabeth , Huang Hsiu-Lin , Decary Stephanie , Zang Guo Hong , Lüscher Thomas F. , Erusalimsky Jorge D.
Published: May 2003

Objective—

Telomerase plays a major role in the control of replicative capacity, a critical property for successful angiogenesis and maintenance of endothelial integrity. In this study, we examined the relationship between telomerase activity and endothelial cell proliferation as well as the regulation of this enzyme by fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor-A (VEGF).

Methods and Results—

Telomerase was repressed in endothelial cells freshly derived from intact endothelium, whereas activity was present during logarithmic growth in culture. In cultured human umbilical vein endothelial cells (HUVECs), mRNA levels of hTERT—the catalytic subunit of telomerase—and enzyme activity decreased reversibly on induction of quiescence. Treatment of quiescent HUVECs with FGF-2 restored telomerase activity in a time- and dose-dependent manner, whereas VEGF had no such effect, although both factors induced comparable mitogenic responses. FGF-2, but not VEGF, upregulated the mRNA levels for hTERT and for the
hTERT
gene transactivation factor Sp1. Serial passage in the presence of individual growth factors accelerated the accumulation of senescent cells in VEGF-treated cultures compared with cultures treated with FGF-2.

Conclusions—

FGF-2, but not VEGF, restores telomerase activity and maintains the replicative capacity of endothelial cells.
Real-Time Imaging of the Dynamics and Secretory Behavior of Weibel-Palade Bodies
Authors: Romani de Wit Thalia , Rondaij Mariska G. , Hordijk Peter L. , Voorberg Jan , van Mourik Jan A.
Published: May 2003

Objective—

Weibel-Palade bodies (WPBs) are specialized secretory granules found in endothelial cells. These vesicles store hormones, enzymes, and receptors and exhibit regulated exocytosis on cellular stimulation. Here we have directly visualized intracellular trafficking and the secretory behavior of WPBs in living cells by using a hybrid protein consisting of von Willebrand factor (vWF), a prominent WPB constituent, and green fluorescent protein (GFP).

Methods and Results—

Immunofluorescence microscopy demonstrated that this chimera was targeted into WPBs. In resting cells, some WPBs seemed motionless, whereas others moved at low speed in a stochastic manner. On stimulation of cells with [Ca
2+
]
i
- or cAMP-raising secretagogues, membrane-apposed patches were formed, suggesting fusion of WPBs with the plasma membrane. Patches remained visible for >20 minutes. This sustained, membrane-associated retention of vWF might play a role in focal adhesion of blood constituents to the endothelium after vascular injury. In addition, stimulation with cAMP-raising agonists resulted in clustering of a subset of WPBs in the perinuclear region of the cell. Apparently, these WPBs escaped secretion. This feature might provide a mechanism to control regulated exocytosis.

Conclusions—

In conclusion, the fusion protein vWF-GFP provides a powerful tool to study, in real time, signal-mediated trafficking of WPBs.
Tribal Governance and Public Administration
Authors: Ortiz James
Published: May 2003

This article examines tribal governance and its relationship with the U.S. government through the lens of laws and treaties. There are more than 550 American Indian and Alaska Native tribes in the United States. Tribes are sovereigns having their own governance structures, with rich cultures that are intertwined with the founding of our nation. This calls for a renewed awareness of tribes by the field of public administration, requiring careful consideration and respect of tribal cultural, historic, and social values, which are an integral part of tribal governance.
Rediscovering Process Values in Employee Grievance Procedures
Authors: Haraway William M.
Published: May 2003

This case study extends legalization research to the public administration field by exploring how the legal environment of complex public organizations transforms social processes for resolving employee disputes. Data analysis revealed that the legal environment constituted by the Commonwealth of Virginia Employee Grievance Program tends to result in the circumvention of immediate supervisors, thereby obviating their positional authority to resolve employee grievances in a nonadversarial way. Findings suggest that grievance procedures designed to mimic judicially legitimate process and procedure alter the way flexibility, trust, and shared meanings govern the essence of organizational relations and result in economic and systemic costs.
The Impact of Americorps Service on Volunteer Participants
Authors: Simon Christopher A. , Wang Changhua
Published: May 2003

Earlier evaluations of Ameri Corps have approached the study of program effects in two general ways. Cost-benefit studies indicate that in select projects the program produces a substantial net benefit. Qualitative studies conclude that the program has a substantial impact on the strength of communities, provides an influx of social capital, and solves unmet human needs. The authors’ analysis focuses on the impact of Ameri Corps on the volunteer members. In a 2-year preservice-postservice analysis they found that the members become more active in community groups. Ameri Corps participation may strengthen social capital—participation parallels a significant value shift among participants.
Alexander Hamilton
Authors: Green Richard T.
Published: May 2003

This article describes the foundation of Hamilton’s theory and practice of public administration. That foundation consists of four interconnected pillars: politics, organization design, ethics, and law. These pillars undergird the public administration today but are not recognized as the foundation of the field. We may be entering a period of reform in our conception of the field. If this is so, we will perhaps also reconsider the interpretation of the field’s origins. Hamilton should figure prominently in any such revision for he, more than any other founder, attended to the theory and practice of public administration in the American Republic. We cannot help but practice the craft of public administration in his shadow.
Woodrow Wilson on the History of Government
Authors: Raadschelders Jos C. N.
Published: May 2003

From the days of independence well into the 1920s, much of the American study of government was defined as the study of political, constitutional, and institutional history. The historical and comparative perspective of Woodrow Wilson on government is illustrative of late 19th-century public administration scholarship, which is characterized by a) notions of the organic state and b) the awareness of an emerging administrative state and its centralizing tendencies. In this article the meaning of Wilson’s The State for the development of administrative history and for his philosophy of governance is explored. Is he one of the founders of American administrative history? Is there more continuity or is there more change in his ideas about governance?
The popularization and excommunication of Fred Hoyle's “life-from-space” theory
Authors: Gregory Jane
Published: May 2003

Fred Hoyle's life-from-space theory has been communicated by Hoyle and other commentators for nearly 50 years in a wide range of media, including science fiction and museums, as well as in the technical and popular press. This analysis uses Lewenstein's “web” model of science communication to demonstrate the connectedness of these media in a web within which life-from-space theory moves from niche to niche as different audiences become significant. Marginalization of the theory as a scientific idea meant a greater prominence in popular culture, and scientific approval made the public sphere redundant. On the basis of this case study, the paper assesses the value of the web as a research tool, and argues for science communication studies to look beyond traditional categories to embrace the wide variety of media and genres that contribute to the construction of science in the public.
“Science,”“common sense,” and DNA evidence: a legal controversy about the public understanding of science
Authors: Lynch Michael , McNally Ruth
Published: May 2003

Law courts are important institutional settings in which public understanding of science is problematic. Courts have struggled with the question of how to handle scientific evidence in a system of justice in which lay jurors are responsible for deciding the facts of the case. Judicial conceptions of science and of jurors' capacities to understand scientific evidence inform decisions in particular cases. Such decisions, in turn, act as precedents that, for better or worse, embed judicial conceptions of public understanding of science into the workings of the legal system. This paper examines an English case in which the difference between “scientific” and “common sense” evidence was explicitly at stake. In this case Regina v. Adams, DNA evidence was used to convict the defendant of rape. The principal item of prosecutorial evidence was a match between DNA profiles developed from the defendant's blood and from semen recovered at the crime scene. Prosecution experts expressed the evidence in probabilistic terms, estimating a probability of one in 200 million that a DNA profile from a randomly chosen unrelated man in the relevant population would match the profile developed from the crime stain. Other so-called “common sense” evidence supported the defendant's not guilty plea. The case was appealed twice in the mid-1990s as the Court of Appeal deliberated over an innovative effort by the defense to counteract the prosecution evidence by converting the non-DNA “common sense” evidence into probability estimates. In its decisions, the Court reinstated a boundary between the “scientific” and “common sense” evidence, arguing that this boundary was necessary to preserve the jury's role as trier of fact. The paper's discussion of the court's boundary work addresses unresolved problems with the place of probability estimates in jury trials.
An overview of surveys on how people view animal experimentation: some factors that may influence the outcome
Authors: Hagelin Joakim , Carlsson Hans-Erik , Hau Jann
Published: May 2003

Many factors may influence the outcome of surveys on how people view the use of animals in research. Some aspects are related to the instrument used, whereas others are related to the characteristics of the respondents. Conducted in Western countries, the study is primarily a review of 56 surveys targeting scientists, students, and the public. Surveys were obtained from searching online databases and reference lists, or directly from authors whose surveys were not otherwise available. Factors related to the instrument listed include the questionnaire used and wording of questions. Factors related to the respondent include age, gender, upbringing, religion, knowledge, education, and practical experience. Results demonstrate that there was great discrepancy in acceptance/opposition estimations reported in different surveys. It is concluded that interpretation and comparison of results from different surveys should be made with caution.
A chip off the old block? Lay understandings of inheritance among men and women in mid-life
Authors: Emslie Carol , Hunt Kate , Watt Graham
Published: May 2003

Recent developments in molecular biology open up the possibility of being able to provide more precise genetic information to individuals. It is therefore important to examine lay understandings of the mechanisms of inheritance. Most studies to date have focused on the beliefs of families with single gene disorders. We explored lay understandings among respondents from “ordinary” families by conducting semi-structured interviews with 61 men and women subsampled from a large community-based study. Respondents found it easy to talk about inheritance within their own family context, given that discussions about inheritance from part of family culture. They constructed family narratives using artifacts such as family photographs, and they used phrases such as “double” and “spitting image” to emphasize likeness between relatives and to reinforce continuity across generations. However, respondents were more uncertain when asked to talk in more abstract terms about the mechanisms that underlie inheritance. There was some evidence to support the hypothesis that women are the `kinkeepers' of the family. As scientific understandings of the “new genetics” proliferate, it is important to recognize that they do not simply fill a vacuum, but must fit into pre-existing social relationships and contexts.
Big science, little news: science coverage in the Italian daily press, 1946-1997
Authors: Bucchi Massimiano , Mazzolini Renato G.
Published: May 2003

This article reports on a content analysis of science coverage by the leading Italian newspaper, Il Corriere della Sera, over a period of fifty years. Results show an expansion of such coverage over time, although it was increasingly “institutionalized” in new sections devoted to science and medicine. The typical science story can be described as dealing with biomedical issues, referring to a geographical context outside Italy, relying on uncontested scientific expertise and presenting the consequences of science activity in a positive fashion.

However, deeper analysis suggests the presence of a marked dualism between two distinct journalistic genres: (1) “science-popularization,” which is characteristic of special sections, overwhelmingly dominated by biomedical topics, depicting science as straightforward, consensual, and bringing improvement to people's lives; and (2) “science as news,” dealing more frequently with other fields such as the physical sciences, paying closer attention to controversy and to the harmful consequences of scientific enterprise. A comparison with similar studies in other countries is also presented.