bluuebunny/crossref_metadata_2025 huggingface dataset:
The Pathogenesis of Foam Cell Formation
Authors: Jones Nancy L. , Reagan Jerry W. , Willingham Mark C.
Published: June 2011

Abstract
—Previously, modified LDLs were shown to stimulate macropinocytosis in pigeon macrophages. Simultaneous intracellular trafficking of LDL and AcLDL, differentially labeled with colloidal gold, was done to determine whether uptake of LDL, which does not cause foam cell formation, was internalized via a separate route from AcLDL, which stimulates foam cell formation. AcLDL and LDL were followed at either low (12 μg/mL) concentrations near the saturation of high affinity binding sites or high (50 to 150 μg/mL) lipoprotein concentrations used to induce foam cell formation. The colloidal gold distribution and percentage of co-labeling as observed by transmission electron microscopy were determined for organelles involved with coated-pit endocytosis or macropinocytosis. LDL simultaneously incubated with AcLDL on macrophages at the low concentration was predominately internalized via coated-pit endocytosis. AcLDL was internalized via both coated-pit endocytosis and macropinocytosis at low concentration. At higher lipoprotein concentrations (50 to 150 μg/mL), AcLDL continued to be internalized via macropinocytosis. Interestingly, a significant portion of the co-incubated LDL, at high concentrations, also trafficked via macropinocytosis. LDL internalized by macropinosomes at high lipoprotein concentrations suggests that AcLDL-stimulated macropinocytosis might increase uptake of co-incubated lipoproteins. When
125
I-LDL was incubated with cold AcLDL, LDL degradation at 37°C doubled, without a corresponding increase in cell association or total binding of LDL at 4°C. These studies suggest that modified LDL-stimulated macropinocytosis is a mechanism for increased degradation of co-incubated LDL potentially leading to foam cell formation.
Effects of Coronary Heart Disease Risk Factors on Atherosclerosis of Selected Regions of the Aorta and Right Coronary Artery
Authors: McGill Henry C. , McMahan C. Alex , Herderick Edward E. , Tracy Richard E. , Malcom Gray T. , Zieske Arthur W. , Strong Jack P.
Published: June 2011

Abstract
—We examined topographic distributions of atherosclerosis and their relation to risk factors for adult coronary heart disease in right coronary arteries and abdominal aortas of more than 2000 autopsied persons 15 through 34 years of age. We digitized images of Sudan IV–stained fatty streaks and of manually outlined raised lesions and computed the percent surface area involved by each lesion in each of 6 regions of each artery. In abdominal aortas of 15- to 24-year-old persons, fatty streaks involve an elongated oval area on the dorsolateral intimal surface and another oval area in the middle third of the ventral surface. Raised lesions in 25- to 34-year-old persons involve an oval area in the distal third of the dorsolateral intimal surface. In other areas of the abdominal aortas of older persons, fatty streaks occur but raised lesions are rare. In the right coronary arteries of 15- to 24-year-old persons, fatty streaks are most frequent on the myocardial aspect of the first 2 cm. Raised lesions follow a similar pattern in 25- to 34-year-old persons. High non-HDL cholesterol and low HDL cholesterol concentrations are associated with more extensive fatty streaks and raised lesions in all regions of both arteries. Smoking is associated with more extensive fatty streaks and raised lesions of the abdominal aorta, particularly in the dorsolateral region of the distal third of the abdominal aorta. Hypertension is not associated with fatty streaks in whites or blacks but is associated with more extensive raised lesions in blacks. Risk factor effects on arterial regions that are vulnerable to lesions are ≈25% greater than risk factor effects assessed over entire arterial segments. These risk factor effects on vulnerable sites emphasize the need for risk factor control during adolescence and young adulthood to prevent or delay the progression of atherosclerosis.
Genetic Mechanisms of Age Regulation of Blood Coagulation
Authors: Kurachi Kotoku , Kurachi Sumiko
Published: June 2011

Abstract
—Blood coagulation capacity increases with age in healthy individuals, apparently because of increases in the plasma concentration of most procoagulant factors. This phenomenon may play an important role in the advancing age–associated increase of cardiovascular diseases and thrombosis. Through longitudinal analyses of transgenic mice, we recently identified 2 critical age-regulatory elements, AE5′ and AE3′, which are together essential for age regulation of the normal human factor IX (hFIX) gene. AE5′, present in the long interspersed repetitive element–derived sequence of the 5′ upstream region, containing polyomavirus enhancer activator-3 or a closely related element, is responsible for age-stable expression of the gene and functions in a position-independent manner. AE3′, present in the middle of the 3′ untranslated region, is responsible for age-associated elevation of hFIX mRNA levels in the liver. Presence of both AE5′ and AE3′ is needed to recapitulate normal age regulation of the hFIX gene. Because factor IX clearance from the circulation is not significantly affected by age, age regulation of hFIX levels is achieved primarily by a combination of stabilization of gene transcription and age-dependent increases in the mRNA levels, which are presumably due to increasing mRNA stabilization. The stage is now set for further systematic studies of the genetic and molecular mechanisms of age regulation of other key coagulation and anticoagulation factors in hopes of understanding the overall age regulation of blood coagulation.
Clinically Used Estrogens Differentially Inhibit Human Aortic Smooth Muscle Cell Growth and Mitogen-Activated Protein Kinase Activity
Authors: Dubey Raghvendra K. , Jackson Edwin K. , Gillespie Delbert G. , Zacharia Lefteris C. , Imthurn Bruno , Keller Paul J.
Published: June 2011

Abstract
—Some estrogenic compounds modify vascular smooth muscle cell (SMC) biology; however, whether such effects are mediated in part by estrogen receptors is unknown. The purpose of this study was to evaluate whether the actions of clinically used estrogens on human aortic SMC biology are mediated by estrogen receptors. We examined the effects of various clinically used estrogens in the presence and absence of ICI 182,780, an estrogen receptor antagonist, on cultured human aortic SMC DNA synthesis ([
3
H]thymidine incorporation), cellular proliferation (cell counting), cell migration (modified Boyden chamber), collagen synthesis ([
3
H]proline incorporation), and mitogen-activated protein kinase activity. FCS-induced DNA synthesis, cell proliferation, collagen synthesis, platelet-derived growth factor–induced SMC migration, and mitogen-activated protein kinase activity were significantly inhibited by physiological (10
−9
mol/L) concentrations of 17β-estradiol and low concentrations (10
−8
to 10
−7
mol/L) of 17β-estradiol, estradiol valerate, estradiol cypionate, and estradiol benzoate but not by estrone, estriol, 17α-estradiol, or estrone sulfate. The inhibitory effects of 17β-estradiol and other inhibitory estrogens were completely reversed by 100 μmol/L ICI 182,780, and the rank-order potency of various estrogens to inhibit SMC biology matched their rank-order affinity for estrogen receptors. The inhibitory effects of estrogens on SMC biology are in part receptor-mediated. Because the cardioprotective effects of hormone replacement therapy are most likely mediated by modification of SMC biology, whether hormone replacement therapy protects a given postmenopausal woman against cardiovascular disease will depend partially on the affinity of the estrogen for estrogen receptors in vascular SMCs.
Plasma Concentrations of a Novel, Adipose-Specific Protein, Adiponectin, in Type 2 Diabetic Patients
Authors: Hotta Kikuko , Funahashi Tohru , Arita Yukio , Takahashi Masahiko , Matsuda Morihiro , Okamoto Yoshihisa , Iwahashi Hiromi , Kuriyama Hiroshi , Ouchi Noriyuki , Maeda Kazuhisa , Nishida Makoto , Kihara Shinji , Sakai Naohiko , Nakajima Tadahisa , Hasegawa Kyoichi , Muraguchi Masahiro , Ohmoto Yasukazu , Nakamura Tadashi , Yamashita Shizuya , Hanafusa Toshiaki , Matsuzawa Yuji
Published: June 2011

Abstract
—Adiponectin is a novel, adipose-specific protein abundantly present in the circulation, and it has antiatherogenic properties. We analyzed the plasma adiponectin concentrations in age- and body mass index (BMI)–matched nondiabetic and type 2 diabetic subjects with and without coronary artery disease (CAD). Plasma levels of adiponectin in the diabetic subjects without CAD were lower than those in nondiabetic subjects (6.6±0.4 versus 7.9±0.5 μg/mL in men, 7.6±0.7 versus 11.7±1.0 μg/mL in women;
P
<0.001). The plasma adiponectin concentrations of diabetic patients with CAD were lower than those of diabetic patients without CAD (4.0±0.4 versus 6.6±0.4 μg/mL,
P
<0.001 in men; 6.3±0.8 versus 7.6±0.7 μg/mL in women). In contrast, plasma levels of leptin did not differ between diabetic patients with and without CAD. The presence of microangiopathy did not affect the plasma adiponectin levels in diabetic patients. Significant, univariate, inverse correlations were observed between adiponectin levels and fasting plasma insulin (
r
=−0.18,
P
<0.01) and glucose (
r
=−0.26,
P
<0.001) levels. In multivariate analysis, plasma insulin did not independently affect the plasma adiponectin levels. BMI, serum triglyceride concentration, and the presence of diabetes or CAD remained significantly related to plasma adiponectin concentrations. Weight reduction significantly elevated plasma adiponectin levels in the diabetic subjects as well as the nondiabetic subjects. These results suggest that the decreased plasma adiponectin concentrations in diabetes may be an indicator of macroangiopathy.
Platelet Thrombus Formation on Collagen at High Shear Rates Is Mediated by von Willebrand Factor–Glycoprotein Ib Interaction and Inhibited by von Willebrand Factor–Glycoprotein IIb/IIIa Interaction
Authors: Wu Ya-Ping , Vink Tom , Schiphorst Marion , van Zanten G. Henrita , IJsseldijk Martin J. W. , de Groot Philip G. , Sixma Jan J.
Published: June 2011

Abstract
—We studied the role of von Willebrand Factor (vWF) in platelet thrombus formation in flowing blood by using a perfusion system and mutant forms of vWF lacking either interaction with glycoprotein Ib (GpIb) or with glycoprotein IIb/IIIa (αIIb-β3). These mutants were added to the blood of patients with severe von Willebrand’s disease (vWD) or to normal blood reconstituted with a human albumin solution instead of plasma. This blood was then perfused over collagen type III spray-coated on a glass surface and preincubated for 2 hours with 20 μg/mL plasma vWF. In this way, the adhesion step was mediated by the preincubated plasma vWF bound to collagen type III, whereas thrombus formation was mediated by mutant vWF added to the perfusate. Thrombus formation was absent at all 3 shear rates studied (300, 800, and 2600 s
−1
) when ΔA1-vWF, lacking interaction with GpIb, was added to the perfusate, indicating the importance of GpIb-vWF interaction for thrombus formation. The interaction of vWF and GpIb is currently thought to be possible under physiological conditions in which the conformation of vWF has been changed by adsorption to a surface. Our results regarding the role of GpIb-vWF interaction in thrombus formation suggest that a second mechanism may operate by which a change may occur in GpIb on the surface of adhered platelets either by activation of the molecule or as a consequence of shear stress. Increased thrombus formation was observed when the Arg-Gly-Gly-Ser–vWF, which does not interact with αIIb-β3, was added to vWD blood and perfused at 2600 s
−1
. This increase was not observed in vWD blood at lower shear rates or after addition of Arg-Gly-Gly-Ser–vWF to reconstituted normal blood. Thrombus formation at a high shear rate was largest when either vWF or fibrinogen was present as a single ligand for αIIb-β3 at a high shear rate. When both were present, thrombus formation was decreased. We postulate that thrombus formation is less efficient because of incomplete bridge formation when vWF and fibrinogen are both present as ligands for αIIb-β3.
Hypertriglyceridemic VLDL Downregulates Tissue Plasminogen Activator Gene Transcription Through
cis
-Repressive Region(s) in the Tissue Plasminogen Activator Promoter in Cultured Human Endothelial Cells
Authors: Tabengwa Edlue M. , Benza Raymond L. , Grenett Hernan E. , Booyse Francois M.
Published: June 2011

Abstract
—The relationship between tissue plasminogen activator (tPA) levels and the potential regulation by hypertriglyceridemic very low density lipoprotein (HTG-VLDL) was examined in a human umbilical vein endothelial cell (HUVEC) culture model system. HUVEC cultures were incubated in the absence/presence of HTG-VLDL or normal (NTG)-VLDL (0 to 50 μg/mL) at 37°C for various times (0 to 24 hours), followed by analyses of tPA antigen (ELISA), mRNA (reverse transcription–polymerase chain reaction), endothelial cell surface–localized plasmin generation assays, and nuclear transcription run-on assays. Secreted tPA antigen levels decreased ≈53% (3.3±0.14 versus 6.97±0.42 μg/mL) and mRNA levels decreased ≈70% in HTG-VLDL–treated HUVECs compared with NTG-VLDL–treated and culture medium control cells. Decreased tPA antigen and mRNA expression was associated with a concomitant ≈98% decrease in tPA-mediated plasmin generation in HTG-VLDL–treated HUVEC cultures. Nuclear transcription run-on assays demonstrated that HTG-VLDL decreased tPA gene transcription ≈73% (tPA mRNA/GAPDH mRNA) in cultured HUVECs. To identify and localize the repressive element(s) in the tPA promoter responsive to HTG-VLDL, a tPA promoter/luciferase construct (ptPA222/luc) was generated. HUVECs transiently transfected with this construct were incubated in the absence/presence of HTG-VLDL or NTG-VLDL (20 μg/mL). HTG-VLDL decreased promoter activity ≈52% to 57% in the ptPA222/luc-transfected cells compared with NTG-VLDL–treated or buffer control cells. These results indicate that the 2.2-kb fragment of the promoter and 5′ flanking region of the tPA gene contains the repressive sequences that direct the transcriptional downregulation of the tPA promoter. Data from these studies suggest that the repression of tPA gene expression by HTG-VLDL may contribute to the impaired fibrinolysis often associated with hypertriglyceridemia.
Interleukin-6 Stimulates LDL Receptor Gene Expression via Activation of Sterol-Responsive and Sp1 Binding Elements
Authors: Gierens Hedi , Nauck Markus , Roth Michael , Schinker Renana , Schürmann Christine , Scharnagl Hubert , Neuhaus Gunther , Wieland Heinrich , März Winfried
Published: June 2011

Abstract
—Inflammatory or malignant diseases are associated with elevated levels of cytokines and abnormal low density lipoprotein (LDL) cholesterol metabolism. In the acute-phase response to myocardial injury or other trauma or surgery, total and LDL cholesterol levels are markedly decreased. We investigated the effects of the proinflammatory cytokine interleukin (IL)-6 on LDL receptor (LDL-R) function and gene expression in HepG2 cells. IL-6 dose-dependently increased the binding, internalization, and degradation of
125
I-LDL. IL-6–stimulated HepG2 cells revealed increased steady-state levels of LDL-R mRNA. In HepG2 cells transiently transfected with reporter gene constructs harboring the sequence of the LDL-R promoter extending from nucleotide −1563 (or from nucleotide −234) through −58 relative to the translation start site, IL-6 dose-dependently increased promoter activity. In the presence of LDL, a similar relative stimulatory effect of IL-6 was observed. Studies using a reporter plasmid with a functionally disrupted sterol-responsive element (SRE)-1 revealed a reduced stimulatory response to IL-6. In gel-shift assays, nuclear extracts of IL-6–treated HepG2 cells showed an induced binding of SRE binding protein (SREBP)-1a and SRE binding protein(SREBP)-2 to the SRE-1 that was independent of the cellular sterol content and an induced binding of Sp1 and Sp3 to repeat 3 of the LDL-R promoter. Our data indicate that IL-6 induces stimulation of the LDL-R gene, resulting in enhanced gene transcription and LDL-R activity. This effect is sterol independent and involves, on the molecular level, activation of nuclear factors binding to SRE-1 and the Sp1 binding site in repeat 2 and repeat 3 of the LDL-R promoter, respectively.
Natural History and Topographic Pattern of Progression of Coronary Calcification in Symptomatic Patients
Authors: Schmermund Axel , Baumgart Dietrich , Möhlenkamp Stefan , Kriener Paul , Pump Heiko , Grönemeyer Dietrich , Seibel Rainer , Erbel Raimund
Published: June 2011

Abstract
—Electron-beam CT may assess the progression of coronary atherosclerosis by visualizing changes in calcification. The present investigation analyzes (1) the rate of progression of calcification in symptomatic patients, (2) the topographic pattern, and (3) the influence of baseline plaque burden and risk factors. Progression of calcification during a mean (median) interval of 18 (15) months was measured in 102 symptomatic outpatients (aged 59±9 years, 80% male) with calcification. In 4 patient groups with a baseline total score (Agatston criteria) of 1 to 30, >30 to 100, >100 to 400, and >400, the median was 3.1, 26.1, 58.9, and 109.7, respectively, for absolute annual progression of the score (
P
<0.05) and 57%, 49%, 32%, and 15%, respectively, for relative progression (
P
<0.05). On the coronary segmental level, changes were largely restricted to typical predilection sites of coronary atherosclerosis. The presence of angiographically defined coronary narrowing influenced absolute, but not relative, progression. Of the risk factors, only low density lipoprotein cholesterol levels showed a trend, although not significant, for predicting progression. These data indicate that baseline plaque burden determines the rate of progression of calcification. This appears to be a coronary systemic process, reflecting the natural history of coronary atherosclerosis.
Photodynamic Therapy With Motexafin Lutetium Induces Redox-Sensitive Apoptosis of Vascular Cells
Authors: Chen Zhiping , Woodburn Kathryn W. , Shi Can , Adelman Daniel C. , Rogers Campbell , Simon Daniel I.
Published: June 2011

Abstract
—Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The combination of photosensitizer and illumination, known as photodynamic therapy (PDT), has been shown to reduce atheroma formation in animal models and is under clinical investigation. However, the effects of PDT with motexafin lutetium on isolated vascular cells are unknown. This study was designed to characterize the effects of PDT on vascular cell viability and to define the cell-death pathway for this agent. Fluorescence microscopy of RAW macrophages and human vascular smooth muscle cells revealed time-dependent uptake of motexafin lutetium. Illumination of motexafin lutetium–loaded cells with 732-nm light (2 J/cm
2
) impaired cellular viability and growth (IC
50
5 to 20 μmol/L). Depletion of intracellular glutathione potentiated (
P
=0.035) and the addition of antioxidant
N
-acetylcysteine attenuated (
P
=0.002) cell death, suggesting that the intracellular redox state influences motexafin lutetium action. PDT was associated with the loss of mitochondrial membrane potential, mitochondrial release of cytochrome
c
, and caspase activation. PDT promoted phosphatidylserine externalization and induced apoptotic DNA fragmentation, with the number of apoptotic cells increasing from 7±2% to 34±3% of total cells. Reducing plaque cellularity by the induction of apoptosis may be one mechanism by which PDT reduces plaque burden, possibly modulates plaque vulnerability, and inhibits restenosis in vivo.
Lysophosphatidylcholine Induces Early Growth Response Factor-1 Expression and Activates the Core Promoter of PDGF-A Chain in Vascular Endothelial Cells
Authors: Morimoto Masafumi , Kume Noriaki , Miyamoto Susumu , Ueno Yasushi , Kataoka Hiroharu , Minami Manabu , Hayashida Kazutaka , Hashimoto Nobuo , Kita Toru
Published: June 2011

Abstract
—Lysophosphatidylcholine (lyso-PC), a polar phospholipid that is increased in atherogenic lipoproteins and atherosclerotic lesions, has been shown to transcriptionally induce the expression of endothelial genes relevant to atherogenesis. In cultured bovine aortic endothelial cells (BAECs), we show that lyso-PC induces the expression of early growth response factor (Egr)-1 and thereby activates the proximal promoter of the platelet-derived growth factor (PDGF)-A chain located 55 to 71 bp upstream from the transcription start site, which has been shown to be crucial for PDGF-A chain expression induced by fluid shear stress and fibroblast growth factor-1. Northern blot analyses showed that lyso-PC (10 to 20 μmol/L) transiently (30 minutes to 1 hour) induced expression of Egr-1 mRNA. Induced expression of Egr-1 mRNA, which was associated with increased amounts of Egr-1 protein in nuclei, preceded PDGF-A chain mRNA induction in lyso-PC–activated BAECs. Nuclear runoff assay revealed that lyso-PC stimulates transcription of the Egr-1 gene. Transient transfection of the oligonucleotide corresponding to the proximal promoter of the PDGF-A chain (oligo A) linked to the luciferase reporter gene revealed that lyso-PC can activate the core promoter of the PDGF-A chain by 5-fold. Insertion of a guanine at 3 sites in the oligo A abolished the lyso-PC–induced increases in luciferase activities. Electrophoretic mobility shift assay with use of radiolabeled oligo A showed a lyso-PC–inducible shift band, which was suppressed by excess amounts of unlabeled oligo A or an anti–Egr-1 antibody. In addition, lyso-PC–induced Egr-1 expression was inhibited by PD98059, a specific inhibitor of mitogen-activated protein kinase kinase-1 (MEK1), suggesting that lyso–PC-induced expression of Egr-1 depends on the MEK1/extracellular signal–regulated kinase pathway. Taken together, transcriptional activation of Egr-1–dependent genes by this atherogenic lipid may be a key regulator of atherogenesis.
Retroviral Overexpression of Decorin Differentially Affects the Response of Arterial Smooth Muscle Cells to Growth Factors
Authors: Fischer Jens W. , Kinsella Michael G. , Levkau Bodo , Clowes Alexander W. , Wight Thomas N.
Published: June 2011

Abstract
—Decorin is a member of the family of small leucine-rich proteoglycans that are present in blood vessels and synthesized by arterial smooth muscle cells (ASMCs). This proteoglycan accumulates in topographically defined regions of atherosclerotic lesions and may play a role in the development of this disease. However, little is known about whether decorin has specific effects on the cellular events that contribute to atherosclerotic lesion formation. In the present study, rat ASMCs were transduced with a retroviral vector (LDSN) that carries the bovine decorin gene. Compared with vector control cells (LXSN), these cells constitutively overexpress decorin, as verified by Northern and Western analysis and by metabolic labeling. Experiments were performed to examine the responsiveness of decorin-overexpressing rat ASMCs to platelet-derived growth factor (PDGF) and transforming growth factor-β1 (TGF-β1), 2 growth factors that affect cell proliferation and extracellular matrix production in atherosclerosis. Decorin-overexpressing cells had decreased [
3
H]thymidine incorporation into DNA and increased the levels of the cyclin-dependent kinase inhibitors p21 and p27 in the first 24 hours of response to serum and PDGF-BB. However, these effects of decorin were not apparent at 48 or 72 hours after plating and did not result in reduced growth of decorin-overexpressing cells in response to serum and PDGF-BB. In contrast, the growth response of decorin-overexpressing ASMCs to TGF-β1, as well as the expression of TGF-β1–responsive genes, such as plasminogen activator inhibitor-1 and versican (an extracellular matrix proteoglycan), was diminished. These results indicate that decorin selectively inhibits the responsiveness of rat ASMCs to TGF-β1 and suggests that the induction of constitutive decorin overexpression by ASMCs in vivo may have therapeutic value in the inhibition of TGF-β1–mediated effects on the development of atherosclerotic lesions.
Cadmium Accumulation in Aortas of Smokers
Authors: Abu-Hayyeh Shadi , Sian Minder , Jones Keith G. , Manuel Ari , Powell Janet T.
Published: June 2011

Abstract
—Abdominal aortic aneurysm is a smoking-related disorder. Cadmium, inhaled from cigarettes, may accumulate in the aorta and facilitate weakening of the aorta through adverse effects on smooth muscle cell metabolism. Cadmium was measured by atomic absorption spectrometry in infrarenal aortas from 13 patients with abdominal aortic aneurysm and from 17 age- and sex-matched patients with normal-diameter abdominal aorta. Total cadmium content was associated with smoking, assessed as pack-years (
r
=0.54,
P
=0.004), but was similar in aneurysmal and undilated aortas. The cadmium content (mean±SE) was higher in the media (3.25±0.53 ng/mg dry wt, 7±1.2 μmol/L) than in the intima or adventitia (1.14±0.24 and 1.87±0.38 ng/mg dry wt, respectively; ANOVA,
P
<0.005). There was a strong correlation between medial cadmium content and pack-years of smoking (
r
=0.87,
P
<0.001). In aortic smooth muscle cells cultured on fibrillar collagen, cadmium inhibited DNA synthesis and collagen synthesis and diminished cell numbers (IC
50
2 μmol/L, 6 μmol/L, and 6 μmol/L, respectively), but higher concentrations of cadmium were required for upregulation of metallothionein (EC
50
23 μmol/L). The cadmium content of the aorta increases in direct proportion to the pack-years of cigarettes smoked, with selective accumulation in the medial layer. However, the cadmium content of aneurysmal aortas was not higher than that of nondilated aortas for patients with matched smoking history. In smokers, the level of cadmium accumulation is probably sufficient to impair the viability of cultured smooth muscle cells. Similar mechanisms could underlie the development of degenerative aortic disease in smokers.
Enzymatically Degraded LDL Preferentially Binds to CD14
high
CD16
+
Monocytes and Induces Foam Cell Formation Mediated Only in Part by the Class B Scavenger-Receptor CD36
Authors: Kapinsky Michael , Torzewski Michael , Büchler Christa , Duong Chinh Quoc , Rothe Gregor , Schmitz Gerd
Published: June 2011

Abstract
—Heterogeneity of peripheral blood monocytes is characterized by specific patterns in the membrane expression of Fc γ-receptor III (FcγRIII/CD16) and the lipopolysaccharide receptor (LPS receptor CD14), allowing discrimination of distinct subpopulations. The aim was to analyze the correlation of these phenotypic differences to the early interaction of freshly isolated monocytes with modified lipoproteins by the use of either enzymatically degraded low density lipoprotein (E-LDL), acetylated low density lipoprotein (ac-LDL), oxidized low density lipoprotein (ox-LDL), or native low density lipoprotein. Highest E-LDL binding was observed on CD14
high
CD16
+
monocytes as determined by flow cytometry, suggesting a selective interaction of E-LDL with distinct subpopulations of monocytes. E-LDL induced rapid foam cell formation both in predifferentiated monocyte-derived macrophages and, in contrast to ac-LDL or ox-LDL, also in freshly isolated peripheral blood monocytes. This was accompanied by upregulation of the 2 class B scavenger receptors CLA-1/SR-BI (CD36 and LIMPII Analogous-1/scavenger receptor type B class I) and CD36. Cellular binding and uptake of E-LDL was neither competed by ac-LDL nor the class A scavenger-receptor inhibitor polyinosinic acid but was partially inhibited by an excess of ox-LDL. In predifferentiated monocyte-derived macrophages, an anti-CD36 antibody inhibited cellular binding and uptake of E-LDL by ≈20%, suggesting that recognition of these hydrolase-modified low density lipoprotein particles is mediated only in part by the class B scavenger receptor CD36.
Coagulation Activity and Clinical Outcome in Unstable Coronary Artery Disease
Authors: Oldgren J. , Linder R. , Grip L. , Siegbahn A. , Wallentin L.
Published: June 2011

Abstract
—In the current study, we investigated molecular markers of coagulation activity, ie, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT) complex, soluble fibrin (SF), and D-dimer, and their relation to death, myocardial infarction, and refractory angina during and after anticoagulant treatment in unstable coronary artery disease. Patients with unstable coronary artery disease (N=320) were randomized to a 72-hour infusion with either inogatran, a low-molecular-mass direct thrombin inhibitor, or unfractionated heparin. During the 30-day follow-up, a 40% lower event rate was seen in patients with high compared with low baseline levels of TAT or SF. High baseline levels of coagulation activity were correlated with a larger decrease during treatment. Patients with decreased compared with raised F1+2 or TAT levels after 6 hours of treatment had a 50% lower event rate at 30 days (F1+2,
P
=0.04; TAT,
P
=0.02). At the cessation of antithrombin treatment, there was a clustering of cardiac events that tended to be related to a rise in the levels of TAT and the other markers. During long-term follow-up (median, 29 months), there was a relation between higher baseline levels of D-dimer (
P
=0.003) and increased mortality. High baseline levels of molecular markers of coagulation activity might identify patients with a thrombotic condition (as the major cause of instability) who are good responders to anticoagulant therapy, with a larger decrease in coagulation activity during treatment and a decreased risk of ischemic events. However, this early benefit is lost during long-term follow-up when high baseline levels of coagulation activity are associated with a raised risk of early reactivation and increased mortality.
Linked Chromosome 16q13 Chemokines, Macrophage-Derived Chemokine, Fractalkine, and Thymus- and Activation-Regulated Chemokine, Are Expressed in Human Atherosclerotic Lesions
Authors: Greaves David R. , Häkkinen Tomi , Lucas Andrew D. , Liddiard Kate , Jones Emma , Quinn Carmel M. , Senaratne Jawaharlal , Green Fiona R. , Tyson Kerry , Boyle Joe , Shanahan Cathy , Weissberg Peter L. , Gordon Siamon , Ylä-Hertualla Seppo
Published: June 2011

Abstract
—Chemokines are important mediators of macrophage and T-cell recruitment in a number of inflammatory pathologies, and chemokines expressed in atherosclerotic lesions may play an important role in mononuclear cell recruitment and macrophage differentiation. We have analyzed the expression of the linked chromosome 16q13 genes that encode macrophage-derived chemokine (MDC/CCL22), thymus- and activation-regulated chemokine (TARC/CCL17), and the CX
3
C chemokine fractalkine (CX
3
CL1) in primary macrophages and human atherosclerotic lesions by reverse transcription–polymerase chain reaction and immunohistochemistry. We show that macrophage expression of the chemokines MDC, fractalkine, and TARC is upregulated by treatment with the Th2-type cytokines interleukin-4 and interleukin-13. High levels of MDC, TARC, and fractalkine mRNA expression are seen in some, but not all, human arteries with advanced atherosclerotic lesions. Immunohistochemistry shows that MDC, fractalkine, and TARC are expressed by a subset of macrophages within regions of plaques that contain plaque microvessels. We conclude that MDC, fractalkine, and TARC, which are chromosome 16q13 chemokines, could play a role in mononuclear cell recruitment into atherosclerotic lesions and influence the subsequent inflammatory response. Macrophage-expressed chemokines upregulated by interleukin-4 may be useful surrogate markers for the presence of Th2-type immune responses in human atherosclerotic lesions.
Estrogen-mediated cytoplasmic and nuclear distribution of rat cardiovascular estrogen receptors.
Authors: Lin A L , Shain S A
Published: June 2011

We used either the synthetic estrogen R2858 (moxestrol) or estradiol-17 beta to characterize estrogen receptors in cytoplasmic (R2858) and nuclear (estradiol-17 beta) preparations from rat aorta and myocardium. Relative steroid specificity studies showed that only estrogens were effective inhibitors of R2858 or estradiol-17 beta binding to aortic and myocardial estrogen receptors, whereas androgens, progestins, and cortisol were ineffective inhibitors. Low ionic strength sucrose density gradient analyses showed that myocardial estrogen receptors that localized in the cytoplasmic fraction migrated as macromolecules with sedimentation coefficients of 8S to 9S. In contrast, two binding components of sedimentation coefficients 8S to 9S and 10S to 11S were characteristic of the estrogen receptors localized in aortic cytoplasmic preparations. High ionic strength sucrose density gradient analysis showed that aortic and myocardial estrogen receptors localized in the nuclear fraction migrated as macromolecules with sedimentation coefficients of 4S to 6S. Saturation analyses showed that aortic and myocardial cytoplasmic preparations from intact young mature male rats contained 50.6 +/- 12.9 (mean +/- SD) and 51.0 +/- 14.1 fmol receptor/mg DNA, respectively. The respective R2858 dissociation constants were 0.42 and 0.15 nM. Estrogen receptors could not be demonstrated in nuclear preparations from cardiovasculature of intact males. Estradiol-17 beta injection of intact young mature male rats caused "depletion" of aortic and myocardial cytoplasmic fraction estrogen receptors and resulted in the appearance of 51.9 +/- 21.0 and 36.9 +/- 9.5 fmol receptor/mg DNA in the corresponding nuclear fractions. The respective estradiol-17 beta dissociation constants were 1.56 and 0.71 nM. Increased estrogen receptor content of cardiovascular nuclear fractions of estradiol-17 beta injected male rats correlated well with the concomitant decreased cytoplasmic fraction receptor content. The ability of estradiol-17 beta to affect localization of cardiovascular estrogen receptors between cytoplasmic and nuclear fractions suggests these estrogen receptors are physiologically functional and indicates that estrogen may directly regulate cardiovascular cell function.
Injury and repair of endothelium at sites of flow disturbances near abdominal aortic coarctations in rabbits.
Authors: Langille B L , Reidy M A , Kline R L
Published: June 2011

The acute and chronic effects of flow disturbances on arterial endothelium were studied by locally constricting the diameter of the rabbit abdominal aorta by 62% + 2.4% (mean +/- SE). This procedure produced a region of elevated shear stress immediately upstream from the coarctation. A region of small irregular vortices was formed in the first 5 to 7 mm downstream, whereas an annular vortex was observed in the region from 2.0 to 2.5 cm further downstream. Morphologic changes to the endothelium near these coarctations were assessed by scanning electron microscopy; endothelial cell replication rates as a function of time after coarctation were monitored with 3H-thymidine. These studies established that profound alterations in endothelial cell shape caused by changes in local flow conditions immediately downstream from coarctations are primarily the result of alterations in morphology of pre-existing cells, rather than the proliferation of new cells with altered morphology. Definitive morphologic evidence of injury to endothelium was not seen at any sites after coarctation. Indeed, any early injury to endothelium caused by the flow disturbances was not sufficiently severe to cause a significant increase in endothelial cell turnover rate during the first week of coarctation. On the other hand, we observed a major increase in cell turnover (over 100-fold) by 30 days after coarctation at sites immediately upstream and immediately downstream of the coarctation. This finding suggests that flow-induced trauma can ultimately injure the cell sufficiently to cause cell death if the source of injury is persistent. Finally, we demonstrated that the high shear stress immediately upstream from the coarctation and the secondary flow disturbances immediately downstream can retard migration of endothelial cells into sites of injury, whereas repair was enhanced in the region of the primary annular vortex.(ABSTRACT TRUNCATED AT 250 WORDS)
Correlates of high density lipoprotein cholesterol and apolipoprotein A-I levels in children. The Bogalusa Heart Study.
Authors: Freedman D S , Srinivasan S R , Shear C L , Webber L S , Chiang Y K , Berenson G S
Published: June 2011

Levels of high density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I) may provide independent information concerning cardiovascular disease risk. Therefore, possible correlates of HDL-C and apo A-I levels were studied in 2827 5- to 17-year-olds from a biracial community, and the possible differences in these relationships were assessed. The characteristics examined included sexual maturation, plasma levels of glucose and insulin, obesity, reported oral contraceptive use, alcohol consumption, and cigarette smoking. In addition, levels of endogenous sex hormones (testosterone, estrogen, and progesterone) were measured in 515 adolescent males. HDL-C and apo A-I levels showed different (p less than 0.001) relationships with both obesity and oral contraceptive use. Increases in subscapular skinfold thickness corresponded more closely to decreases in HDL-C, rather than apo A-I, levels; the relationship with HDL-C was probably mediated by triglyceride levels. In contrast, oral contraceptive use was associated with increases in mean levels of apo A-I (8 mg/dl, whites; 16 mg/dl, blacks), but with only very small changes in HDL-C. (High-estrogen oral contraceptives were related most closely to increases in levels of both HDL-C and apo A-I). Levels of both HDL-C and apo A-I were similarly related to sexual maturation and levels of testosterone (negatively in boys), cigarette smoking (negatively), and alcohol intake (positively). Since levels of apo A-I independently of HDL-C may indicate an increased risk of cardiovascular disease, characteristics related to apo A-I levels should be further examined.
Inhibition of atherosclerosis associated with reduction of arterial intramural stress in rabbits.
Authors: Thubrikar M J , Baker J W , Nolan S P
Published: June 2011

Atherosclerotic lesions commonly develop at arterial branch sites, which are also the sites of high arterial intramural stress produced by intraluminal pressure. We investigated the effect of reduced intramural stress on the development of atherosclerotic lesions. We exposed the origin of the left renal artery in five rabbits and the aortic bifurcation in another five, lowered the mean arterial pressure to 35 to 45 mm Hg, and poured a dental acrylic liquid around the branch to form a rigid cast. When the rabbits recovered and the arterial pressure increased to normal, the casts prevented the arteries from expanding, thereby maintaining a low intramural stress. These rabbits plus two unoperated, two sham-operated, two with silicone rubber casts placed at similar pressures, and four with casts placed at 95 mm Hg pressure were given a 2% cholesterol-enriched diet for 7 to 11 weeks, and then their arteries were examined. In all rabbits, atherosclerotic lesions developed at the origins of the intercostal, celiac, superior mesenteric, and both renal arteries, and at the aortic bifurcation, with these notable exceptions: no lesions developed at the origins of casted renal arteries or at the casted aortic bifurcations when the cast was placed at a low pressure. Measurements of the diameter and thickness of the aorta in the left renal branch and aortic bifurcation areas, with and without the casts, indicated that there was no significant narrowing of the aortic lumen or thinning of the aorta due to the cast. In conclusion, the inhibition of the development of atherosclerotic lesions appears to be associated with the reduction of arterial intramural stress.
Blood platelets are concentrated near the wall and red blood cells, in the center in flowing blood.
Authors: Aarts P A , van den Broek S A , Prins G W , Kuiken G D , Sixma J J , Heethaar R M
Published: June 2011

Hematocrit and vessel wall shear rate are important factors in the transport and subsequent adherence of platelets to vessel wall subendothelium. When mass transport theory is applied to platelets in flowing blood, the blood is usually considered to be a fluid with platelet and red cell wall concentrations similar to the average tube concentration. With the laser-Doppler technique, we found how red blood cell ghosts and platelets were distributed radially for various hematocrits and wall shear rates. Red cell ghosts are crowded near the axis of the tube, with a local hematocrit higher than the average tube hematocrit, and they decrease steadily toward the wall. In the absence of ghosts, platelets exhibit the 'tubular pinch' effect (rigid particles crowding at 0.6 x tube radius). In the presence of ghosts, the platelets are expelled toward the wall region. This high concentration at the wall increases with higher average tube hematocrit and wall shear rates. Increasing the average tube platelet concentration 10 times causes the wall concentration to increase only three times. The increase in platelet adherence observed with increasing hematocrit and increasing wall shear rate can be partially ascribed to increased platelet concentration near the wall. The observation that the increased platelet concentration does not fully explain the platelet adherence data suggests that platelet transport may also be enhanced by a shear rate-dependent rotary motion.
Beta-very low density lipoprotein pretreatment of endothelial monolayers increases monocyte adhesion.
Authors: Territo M C , Berliner J A , Almada L , Ramirez R , Fogelman A M
Published: June 2011

Treatment of rabbit aortic endothelial cells or human umbilical vein cells for as little as 1 day with 25 micrograms/ml of beta-migrating very low density lipoprotein (beta-VLDL), but not low density lipoprotein (LDL), caused an increased binding of human peripheral blood monocytes to the endothelium. This increase was maximal by 24 hours but was not significant at 4 hours of pre-incubation with beta-VLDL. Neutrophil binding was not significantly stimulated by beta-VLDL treatment of endothelial cells, while endotoxin (LPS) treatment of endothelial cells stimulated both neutrophil and monocyte binding. Antibody to leukocyte function-associated-antigen-1 and to Mo2 inhibited binding to both beta-VLDL-stimulated and LPS-stimulated cells by 25%. The fact that both rabbit and human cells were stimulated by beta-VLDL to bind human monocytes suggests that some mechanisms regulating binding are conserved between species. These studies suggest that beta-VLDL acts like a chronic inflammatory mediator to cause a sustained increase in binding of monocytes to the endothelium.
Manipulation of ascending aortic pressure and flow wave reflections with the Valsalva maneuver: relationship to input impedance.
Authors: Murgo J P , Westerhof N , Giolma J P , Altobelli S A
Published: June 2011

Dramatic changes in the shape of pulsatile ascending aortic pressure and flow wave forms occur during the Valsalva maneuver in man. To study these changes, aortic pressure and flow signals were recorded in eight patients using a multisensor catheter. Aortic input impedance was derived during the control, strain and postrelease phases of the Valsalva maneuver. During control, well-defined minima and maxima occurred in the spectral plots of impedance moduli. This pattern was accentuated during the postrelease phase. In contrast, input impedance during strain was almost equal to the characteristic impedance for all harmonics. These results imply that during the control and postrelease phases, strong reflections return to the ascending aorta, but during the strain phase, reflections are minimal, absent or more diffuse. From wave transmission theory, it also follows that pulsatile pressure and flow wave forms should be similar in shape in the absence of reflections and dissimilar in the presence of reflections. This was observed in all eight patients. By provoking changes in the arterial tree during the Valsalva maneuver, the magnitude and timing of wave reflections were significantly altered, resulting in marked changes in the shape of pulsatile aortic pressure and flow wave forms. This study demonstrates the importance of reflections in determining the shape of the arterial pulse.
Beat-to-beat left ventricular performance assessed from the equilibrium cardiac blood pool using a computerized nuclear probe.
Authors: Berger H J , Davies R A , Batsford W P , Hoffer P B , Gottschalk A , Zaret B L
Published: June 2011

The feasibility, accuracy and reproducibility of continuous beat-to-beat evaluation of left ventricular performance with a computerized nonimaging scintillation probe was assessed in 71 patients. This portable instrument has enough sensitivity to generate a real-time relative left ventricular volume curve using the labeled equilibrium blood pool without electrocardiographic gating. The probe was positioned at the left ventricular and background regions of interest using a systematic series of computerized algorithms and operator routines that were developed and standardized during the initial phase of this study. In each patient, left ventricular ejection fraction was calculated manually from the strip-chart recording in 10 consecutive sinus beats. Beat-to-beat left ventricular ejection fraction determined by the probe correlated well with first-pass studies obtained using a computerized multicrystal scintillation camera (r = 0.92). There was no systematic over- or underestimation, and the correlation was evident over a wide range of first-pass values (15-81%). There was excellent agreement between initial and repeat analyses (n = 58, r = 0.97) and between initial and repeat studies (n = 48, r = 0.94). The absolute variability of beat-to-beat ejection fraction measurements determined from all 710 beats was +/- 5.9% (expressed in ejection fraction units as +/- 2 SD). This technique should provide a reliable means of addressing pathophysiologic questions that require sampling of data directly on a beat-to-beat basis.
Circulating platelet products in unstable angina pectoris.
Authors: Sobel M , Salzman E W , Davies G C , Handin R I , Sweeney J , Ploetz J , Kurland G
Published: June 2011

In 19 patients with unstable angina pectoris at rest, plasma levels of the platelet-derived proteins beta-thromboglobulin and platelet factor 4 were significantly elevated in blood samples obtained during or within 4 hours after episodes of angina, but were usually normal during quiescent intervals. Plasma levels of the arachidonic acid metabolite thromboxane B2 were less clearly related to angina, and there was no association of angina with levels of the coagulation product fibrinopeptide A. This demonstration of an association of platelet activation and secretion with unstable angina pectoris by radioimmunoassay of circulating platelet constituents offers a new approach to assessment of therapy in ischemic heart disease and suggests that agents that alter platelet function should be evaluated in patients with unstable angina.