bluuebunny/crossref_metadata_2025 huggingface dataset:
Statins Have Biphasic Effects on Angiogenesis
Authors: Weis Michael , Heeschen Christopher , Glassford Alec J. , Cooke John P.
Published: July 2002

Background

—

Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo.

Methods and Results

—

Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 μmol/L) but significantly inhibited at high statin concentrations (0.05 to 1 μmol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg · kg
−1
· d
−1
) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg · kg
−1
· d
−1
). Despite the fact that high-dose statin treatment was effective at reducing lipid levels in hyperlipidemic apolipoprotein E–deficient mice, it impaired rather than enhanced angiogenesis. Finally, high-dose cerivastatin decreased tumor growth and tumor vascularization in a murine Lewis lung cancer model.

Conclusions

—

HMG-CoA reductase inhibition has a biphasic dose-dependent effect on angiogenesis that is lipid independent and associated with alterations in endothelial apoptosis and vascular endothelial growth factor signaling. Statins have proangiogenic effects at low therapeutic concentrations but angiostatic effects at high concentrations that are reversed by geranylgeranyl pyrophosphate. At clinically relevant doses, statins may modulate angiogenesis in humans via effects on geranylated proteins.
Selective Matrix Metalloproteinase Inhibition Reduces Left Ventricular Remodeling but Does Not Inhibit Angiogenesis After Myocardial Infarction
Authors: Lindsey Merry L. , Gannon Joseph , Aikawa Masanori , Schoen Frederick J. , Rabkin Elena , Lopresti-Morrow Lori , Crawford Jamie , Black Shawn , Libby Peter , Mitchell Peter G. , Lee Richard T.
Published: July 2002

Background

—

Broad inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling after myocardial infarction (MI). However, it is not clear if selective MMP inhibition strategies will be effective or if MMP inhibition will impair angiogenesis after MI.

Methods and Results

—

We used a selective MMP inhibitor (MMPi) that does not inhibit MMP-1 in rabbits, which, like humans but unlike rodents, express MMP-1 as a major collagenase. On day 1 after MI, rabbits were randomized to receive either inhibitor (n=10) or vehicle (n=8). At 4 weeks after MI, there were no differences in infarct size or collagen fractional area. However, MMPi reduced ventricular dilation. The increase in end-diastolic dimension from day 1 to week 4 was 3.1±0.5 mm for vehicle versus 1.3±0.3 mm for MMPi (
P
<0.01). The increase in end-systolic dimension was 2.8±0.5 mm for vehicle and 1.3±0.4 mm for MMPi (
P
<0.05). Furthermore, MMPi reduced infarct wall thinning; the minimal infarct thickness was 0.8±0.1 mm for vehicle and 1.6±0.3 mm for MMPi (
P
<0.05). Interestingly, the MMPi group had increased numbers of vessels in the subendocardial layer of the infarct; the number of capillaries was increased in the subendocardial layer (46±4 vessels/field versus 17±3 vessels/field for vehicle;
P
<0.001), and the number of arterioles was also increased (4.0±0.8 vessels/field versus 2.0±0.4 vessels/field for vehicle;
P
<0.05).

Conclusions

—

MMP inhibition attenuates left ventricular remodeling even when the dominant collagenase MMP-1 is not inhibited; furthermore, this selective MMP inhibition appears to increase rather than decrease neovascularization in the subendocardium.
Risk of Myocardial Infarction and Angina in Patients With Severe Peripheral Vascular Disease
Authors: Rossi Elisabetta , Biasucci Luigi M. , Citterio Franco , Pelliccioni Simona , Monaco Claudia , Ginnetti Francesca , Angiolillo Dominick J. , Grieco Gianni , Liuzzo Giovanna , Maseri Attilio
Published: July 2002

Background—

Patients undergoing revascularization procedures for peripheral vascular disease (PVD) have a greatly increased risk for coronary artery disease (CAD) that is predicted only partly by clinical data and cardiovascular risk factors. We investigated whether the prognostic assessment in PVD patients could be improved by preoperative measurements of C-reactive protein (CRP).

Methods and Results—

We assessed clinical and risk factors profiles, Eagle clinical scores, and preoperative CRP serum levels in 51 patients with PVD at Fontaine-Leriche stages II to IV without severe rest ventricular dysfunction or ischemia. During 24 months of follow-up, 17 patients (34%) had fatal (11) or nonfatal (6) myocardial infarction (MI). With univariate logistic regression analysis, only previous history of CAD, Eagle score, and CRP were independently related to MI. At multivariate logistic regression analysis, only CRP values in the upper tertile (<9 mg/L) were significantly associated with MI (
P
<0.05) and identified 65% of cases.

Conclusions—

The high incidence of MI in patients with PVD severe enough to require revascularization is strongly predicted by preprocedural measurements of serum CRP, independent of previous CAD, Eagle score index, and traditional cardiovascular risk factors. These patients may benefit from therapy modulating the inflammatory response.
Increased Risk of Arrhythmic Events in Long-QT Syndrome With Mutations in the Pore Region of the Human Ether-a-go-go–Related Gene Potassium Channel
Authors: Moss Arthur J. , Zareba Wojciech , Kaufman Elizabeth S. , Gartman Eric , Peterson Derick R. , Benhorin Jesaia , Towbin Jeffrey A. , Keating Mark T. , Priori Silvia G. , Schwartz Peter J. , Vincent G. Michael , Robinson Jennifer L. , Andrews Mark L. , Feng Changyong , Hall W. Jackson , Medina Aharon , Zhang Li , Wang Zhiqing
Published: July 2002

Background
—

The hereditary long-QT syndrome is characterized by prolonged ventricular repolarization and a variable clinical course with arrhythmia-related syncope and sudden death. Mutations involving the human ether-a-go-go–related gene (HERG) channel are responsible for the LQT2 form of long-QT syndrome, and in cellular expression studies these mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current (I
Kr
). We investigated the clinical features and prognostic implications of mutations involving pore and nonpore regions of the HERG channel in the LQT2 form of this disorder.

Methods and Results
—

A total of 44 different HERG mutations were identified in 201 subjects, with 14 mutations located in the pore region (amino acid residues 550 through 650). Thirty-five subjects had mutations in the pore region and 166 in nonpore regions. Follow-up extended through age 40 years. Subjects with pore mutations had more severe clinical manifestations of the genetic disorder and experienced a higher frequency (74% versus 35%;
P
<0.001) of arrhythmia-related cardiac events occurring at earlier age than did subjects with nonpore mutations. Multivariate Cox proportional hazard regression analysis revealed that pore mutations dominated the risk, with hazard ratios in the range of 11 (
P
<0.0001) for QTc at 500 ms, with a 16% increase in the pore hazard ratio for each 10-ms increase in QTc.

Conclusion
—

Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations.
Five-Year Risk of Cardiac Mortality in Relation to Initial Severity and One-Year Changes in Depression Symptoms After Myocardial Infarction
Authors: Lespérance François , Frasure-Smith Nancy , Talajic Mario , Bourassa Martial G.
Published: July 2002

Background
—

Although previous research demonstrated an independent link between depression symptoms and cardiac mortality after myocardial infarction (MI), depression was assessed only once, and a dose-response relationship was not evaluated.

Methods and Results
—

We administered the Beck Depression Inventory to 896 post-MI patients during admission and at 1 year. Five-year survival was ascertained using Medicare data. We observed a significant long-term dose-response relationship between depression symptoms during hospitalization and cardiac mortality. Results remained significant after control for multiple measures of cardiac disease severity. Although 1-year scores were also linked to cardiac mortality, most of that impact was explained by baseline scores. Improvement in depression symptoms was associated with less cardiac mortality only for patients with mild depression. Patients with higher initial scores had worse long-term prognosis regardless of symptom changes.

Conclusions
—

The level of depression symptoms during admission for MI is more closely linked to long-term survival than the level at 1 year, particularly in patients with moderate to severe levels of depression, suggesting that the presumed cardiovascular mechanisms linking depression to cardiac mortality may be more or less permanent for them.
Stenting of the Arterial Duct and Banding of the Pulmonary Arteries
Authors: Akintuerk Hakan , Michel-Behnke Ina , Valeske Klaus , Mueller Matthias , Thul Josef , Bauer Juergen , Hagel Karl-Juergen , Kreuder Joachim , Vogt Paul , Schranz Dietmar
Published: July 2002

Background
—

Outcome of patients with hypoplastic left heart (HLH) is mainly influenced by the successful first-step palliation according to the Norwood procedure. An alternative approach is heart transplantation (HTX). The feasibility of ductal stenting in newborns with duct-dependent systemic blood flow and bilateral pulmonary artery banding has been reported. But it remains to be elucidated whether this approach allows a new strategy for patients with HLH.

Methods and Results
—

In patients with various forms of HLH (n=11) and prostaglandin E-1 administration, ductal stenting was performed with balloon expandable Jo stents or Saxx stents. Bilateral pulmonary artery banding was surgically accomplished 1 to 3 days after the transcatheter procedure. Unrestricted blood flow through the interatrial septum was secured by balloon dilatation atrial septotomy, as required. Interventional procedures were performed with no mortality. Stent and ductal patency were achieved for up to 331 days. Two patients underwent HTX, and 8 patients had a palliative 1-stage procedure with reconstruction of the aortic arch and bidirectional cavopulmonary connection at the age of 3.5 to 6 months. There were 2 deaths. One patient with preoperative right heart failure died after the reconstructive surgery, and 1 patient died 4 months after ductal stenting and bilateral banding awaiting HTX.

Conclusions
—

The present study is the first clinical trial showing that stenting the duct followed by bilateral pulmonary artery banding in newborns with HLH allows the combination of neoaortic reconstruction, which is part of first-stage palliation of HLH, with the establishment of a bidirectional cavopulmonary connection. Additionally, it allows the chance for HTX after extended waiting periods.
Suppression of Coronary Artery Spasm by the Rho-Kinase Inhibitor Fasudil in Patients With Vasospastic Angina
Authors: Masumoto Akihiro , Mohri Masahiro , Shimokawa Hiroaki , Urakami Lemmy , Usui Makoto , Takeshita Akira
Published: July 2002

Background

—

Increased activity of Rho-kinase causes hypercontraction of vascular smooth muscle and has been implicated as playing a pathogenetic role in divergent cardiovascular diseases such as coronary artery spasm. We examined whether an intracoronary infusion of fasudil, a selective Rho-kinase inhibitor, would attenuate coronary vasoconstrictor responses to acetylcholine (ACh) in patients with vasospastic angina.

Methods and Results

—

We studied 20 consecutive patients in whom coronary artery spasm was provoked by intracoronary ACh. The patients underwent a second ACh challenge after pretreatment with intracoronary saline (n=5) or fasudil (n=15; 300 μg/min for 15 minutes). Angina and coronary vasospasm were reproducibly induced by the second testing in patients who received saline. In contrast, fasudil markedly attenuated the coronary constriction induced by ACh (
P
<0.001) and prevented the occurrence of chest pain and ischemic ECG changes in all treated patients (both
P
<0.01 versus saline). Fasudil, at the dose used in this study, did not significantly change systemic hemodynamics or baseline coronary blood flow.

Conclusions

—

Fasudil was effective in preventing ACh-induced coronary artery spasm and resultant myocardial ischemia in patients with vasospastic angina. We suggest that this Rho-kinase inhibitor may be a novel therapeutic intervention to treat ischemic coronary syndromes caused by coronary artery spasm.
Nongenomic Mechanisms of Endothelial Nitric Oxide Synthase Activation by the Selective Estrogen Receptor Modulator Raloxifene
Authors: Simoncini Tommaso , Genazzani Andrea R. , Liao James K.
Published: July 2002

Background

—

Nontranscriptional signaling through estrogen receptors (ERs) is important in the cardiovascular system. In particular, estrogen stimulates endothelial NO synthase (eNOS) via the phosphatidylinositol 3-kinase (PI3K) pathway. The selective estrogen receptor modulator (SERM) raloxifene is effective for the treatment of postmenopausal osteoporosis, but its ability to activate eNOS via PI3K is unknown.

Methods and Results

—

Human umbilical vein endothelial cells were cultured in estrogen-deprived, phenol red-free medium. Raloxifene stimulated eNOS in a concentration- and time-dependent manner. Activation of eNOS by raloxifene was blocked by the PI3K inhibitor wortmannin and by the ER antagonist ICI 182,780 but not by transcriptional or translational inhibitors. Coimmunoprecipitation studies demonstrated that, in a ligand-dependent manner, raloxifene increased ERα-associated p85α, p110α, and PI3K activity. This correlated temporally with increases in the serine and threonine phosphorylation and activation of protein kinase Akt.

Conclusions

—

Our findings indicate that nongenomic ER signaling triggered by a SERM leads to a rapid activation of NO synthesis in human endothelial cells. The ability of raloxifene to facilitate ERα-PI3K interaction may provide additional insight into the structure-function relationship of specific SERMs, which promote the nontranscriptional effects of ER.
Natural History of Brugada Syndrome
Authors: Priori Silvia G. , Napolitano Carlo , Gasparini Maurizio , Pappone Carlo , Bella Paolo Della , Giordano Umberto , Bloise Raffaella , Giustetto Carla , De Nardis Roberto , Grillo Massimiliano , Ronchetti Elena , Faggiano Giovanna , Nastoli Janni
Published: July 2002

Background

—

Treatment of patients with Brugada syndrome is complicated by the incomplete information on the natural history of the disease related to the small number of cases reported. Furthermore, the value of programmed electrical stimulation (PES) for risk stratification is highly debated. The objective of this study was to search for novel parameters to identify patients at risk of sudden death.

Methods and Results

—

Clinical data were collected for 200 patients (152 men, 48 women; age, 41±18 years) and stored in a dedicated database. Genetic analysis was performed, and mutations on the
SCN5A
gene were identified in 28 of 130 probands and in 56 of 121 family members. The life-table method of Kaplan-Meier used to define the cardiac arrest-free interval in patients undergoing PES failed to demonstrate an association between PES inducibility and spontaneous occurrence of ventricular fibrillation. Multivariate Cox regression analysis showed that after adjusting for sex, family history of sudden death, and
SCN5A
mutations, the combined presence of a spontaneous ST-segment elevation in leads V
1
through V
3
and the history of syncope identifies subjects at risk of cardiac arrest (HR, 6.4; 95% CI, 1.9 to 21;
P
<0.002).

Conclusions

—

The information on the natural history of patients obtained in this study allowed elaboration of a risk-stratification scheme to quantify the risk for sudden cardiac death and to target the use of the implantable cardioverter-defibrillator.
Angiogenic Gene Therapy (AGENT) Trial in Patients With Stable Angina Pectoris
Authors: Grines Cindy L. , Watkins Matthew W. , Helmer Greg , Penny William , Brinker Jeffrey , Marmur Jonathan D. , West Andrew , Rade Jeffery J. , Marrott Pran , Hammond H. Kirk , Engler Robert L.
Published: July 2002

Background

—

The angiogenic response to myocardial ischemia can be augmented in animal models by gene transfer with the use of a replication defective adenovirus (Ad) containing a human fibroblast growth factor (FGF) gene.

Methods and Results

—

The objectives of the Angiogenic GENe Therapy (AGENT) trial were to evaluate the safety and anti-ischemic effects of 5 ascending doses of Ad5-FGF4 in patients with angina and to select potentially safe and effective doses for subsequent study. Seventy-nine patients with chronic stable angina Canadian Cardiovascular Society class 2 or 3 underwent double-blind randomization (1:3) to placebo (n=19) or Ad5-FGF4 (n=60). Safety evaluations were performed at each visit and exercise treadmill testing (ETT) at baseline and at 4 and 12 weeks. Single intracoronary administration of Ad5-FGF4 seemed to be safe and well tolerated with no immediate adverse events. Fever of <1-day duration occurred in 3 patients in the highest-dose group. Transient, asymptomatic elevations in liver enzymes occurred in 2 patients in lower-dose groups. Serious adverse events during follow-up (mean, 311 days) were not different between placebo and Ad5-FGF4. Overall, patients who received Ad5-FGF4 tended to have greater improvements in exercise time at 4 weeks (1.3 versus 0.7 minutes,
P
=NS, n=79). A protocol-specified, subgroup analysis showed the greatest improvement in patients with baseline ETT ≤10 minutes (1.6 versus 0.6 minutes,
P
=0.01, n=50).

Conclusions

—

Results show evidence of favorable anti-ischemic effects with Ad5-FGF4 compared with placebo, and it appears to be safe. Angiogenic gene transfer with Ad5-FGF4 shows promise as a new therapeutic approach to the treatment of angina pectoris.
Maternal Hypercholesterolemia During Pregnancy Promotes Early Atherogenesis in LDL Receptor-Deficient Mice and Alters Aortic Gene Expression Determined by Microarray
Authors: Napoli Claudio , de Nigris Filomena , Welch John S. , Calara Federico B. , Stuart Robert O. , Glass Christopher K. , Palinski Wulf
Published: July 2002

Background

—

Maternal hypercholesterolemia during pregnancy is associated with markedly enhanced fatty streak formation in human fetal aortas and accelerated progression of atherosclerosis in normocholesterolemic children.

Methods and Results

—

To establish the causal role of maternal hypercholesterolemia in a genetically homogeneous murine model and to test the hypothesis that pathogenic events during fetal development result in persistent changes in arterial gene expression, female LDL receptor-deficient (LDLR
−/−
) mice were fed regular chow or high-fat diets supplemented with 0.075% or 1.25% cholesterol during pregnancy. Lesion sizes were determined in the aortic origin of their chow-fed offspring at 3 months. Maternal hypercholesterolemia more than doubled lesion sizes in male offspring (
P
<0.0001 for the 0.0075% cholesterol group). Microarray analysis of the expression of 11 000 murine genes in the nonatherosclerotic descending aorta by Affymetrix gene chips suggested that 139 genes were significantly regulated in offspring of hypercholesterolemic mothers. A subset of 12 of the upregulated transcripts was subjected to secondary analysis by semiquantitative PCR of pooled RNA and 4 genes were found to be upregulated >1.7-fold. Quantitative PCR for one of these genes using RNA from individual mice yielded similar results. Comparative immunostaining for several of the above genes also indicated increased protein content in offspring of hypercholesterolemic mothers.

Conclusions

—

These findings establish an atherogenic effect of maternal hypercholesterolemia in genetically uniform mice and indicate that changes in aortic gene expression persist long after fetal exposure to hypercholesterolemia. In addition to elucidating pathogenic mechanisms initiated during fetal development, this approach may identify genes in morphologically normal arteries that influence the susceptibility to classical risk factors of atherosclerosis.
Impact of Diabetes on the Risk Stratification Using Stress Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging in Patients With Symptoms Suggestive of Coronary Artery Disease
Authors: Giri Satyendra , Shaw Leslee J. , Murthy Dakshina R. , Travin Mark I. , Miller D. Douglas , Hachamovitch Rory , Borges-Neto Salvadore , Berman Daniel S. , Waters David D. , Heller Gary V.
Published: July 2002

Background
—

Coronary artery disease can develop prematurely and is the leading cause of death among diabetics, making noninvasive risk stratification desirable.

Methods and Results
—

Patients with symptoms of coronary artery disease who were undergoing stress myocardial perfusion imaging (MPI) from 5 centers were prospectively followed (2.5±1.5 years) for the subsequent occurrence of cardiac death, myocardial infarction (MI), and revascularization. Stress MPI results were categorized as normal or abnormal (fixed or ischemic defects and 1, 2, or 3 vessel distribution). Of 4755 patients, 929 (19.5%) were diabetic. Patients with diabetes, despite an increased revascularization rate, had 80 cardiac events (8.6%; 39 deaths and 41 MIs) compared with 172 cardiac events (4.5%; 69 deaths and 103 MIs) in the nondiabetic cohort (
P
<0.0001). Abnormal stress MPI was an independent predictor of cardiac death and MI in both populations. Diabetics with ischemic defects had an increased number of cardiac events (
P
<0.001), with the highest MI rates (17.1%) observed with 3-vessel ischemia. Similarly, a multivessel fixed defect was associated with the highest rate of cardiac death (13.6%) among diabetics. The unadjusted cardiac survival rate was lower for diabetic patients (91% versus 97%,
P
<0.001), but it became comparable once adjusted for the pretest clinical risk and stress MPI results. In multivariable Cox analysis, both ischemic and fixed MPI defects independently predicted cardiac death alone or cardiac death/MI. Diabetic women had the worst outcome for any given extent of myocardial ischemia.

Conclusions
—

In this large cohort of diabetics undergoing stress MPI, the presence and the extent of abnormal stress MPI independently predicted subsequent cardiac events. Using stress MPI in conjunction with clinical information can provide risk stratification of diabetic patients.
β-Adrenergic Stimulation Modulates Ryanodine Receptor Ca
2+
Release During Diastolic Depolarization to Accelerate Pacemaker Activity in Rabbit Sinoatrial Nodal Cells
Authors: Vinogradova Tatiana M. , Bogdanov Konstantin Yu. , Lakatta Edward G.
Published: July 2002

It has long been recognized that activation of sympathetic β-adrenoceptors (β-ARs) increases the spontaneous beating rate of sinoatrial nodal cells (SANCs); however, the specific links between stimulation of β-ARs and the resultant increase in firing rate remain an enigma. In the present study, we show that the positive chronotropic effect of β-AR stimulation is critically dependent on localized subsarcolemmal ryanodine receptor (RyR) Ca
2+
releases during diastolic depolarization (CRDD). Specifically, isoproterenol (ISO; 0.1 μmol/L) induces a 3-fold increase in the number of CRDDs per cycle; a shift to higher CRDD amplitudes (from 2.00±0.04 to 2.17±0.03 F/F
0
;
P
<0.05 [F and F
0
refer to peak and minimal fluorescence]); and an increase in spatial width (from 3.80±0.44 to 5.45±0.47 μm;
P
<0.05). The net effect results in an augmentation of the amplitude of the local preaction potential subsarcolemmal Ca
2+
transient that, in turn, accelerates the diastolic depolarization rate, leading to an increase in SANC firing rate. When RyRs are disabled by ryanodine, β-AR stimulation fails to amplify subsarcolemmal Ca
2+
releases, fails to augment the diastolic depolarization rate, and fails to increase the SANC firing rate, despite preserved β-AR stimulation-induced augmentation of L-type Ca
2+
current amplitude. Thus, the RyR Ca
2+
release acts as a switchboard to link β-AR stimulation to an increase in SANC firing rate: recruitment of additional localized CRDDs and partial synchronization of their occurrence by β-AR stimulation lead to an increase in the heart rate.
Vitamin E Oxidation in Human Atherosclerotic Lesions
Authors: Terentis Andrew C. , Thomas Shane R. , Burr Jeanne A. , Liebler Daniel C. , Stocker Roland
Published: July 2002

Oxidation of low-density lipoproteins (LDL) is a key process in atherogenesis, and vitamin E (α-tocopherol, TOH) has received attention for its potential to attenuate the disease. Despite this, the type and extent of TOH oxidation and its relationship to lipid oxidation in the vessel wall where lesions develop remain unknown. Therefore, we measured oxidized lipids, TOH, and its oxidation products, α-tocopherylquinone (TQ), 2,3- and 5,6-epoxy-α-tocopherylquinones by gas chromatography–mass spectrometry analysis in human lesions representing different stages of atherosclerosis. We also oxidized LDL in vitro to establish “footprints” of TOH oxidation product for different oxidants. The in vitro studies demonstrated that tocopherylquinone epoxides are the major products when LDL is exposed to the one-electron (ie, radical) oxidants, peroxyl radicals, and copper ions, whereas TQ preferentially accumulates with the two-electron (nonradical) oxidants, hypochlorite, and peroxynitrite. In human lesions, the relative extent of TOH oxidation was maximal early in the disease where it exceeded lipid oxidation. Independent of the disease stage, TQ was always the major oxidation product with all products together representing <20% of the total TOH present, and the oxidation product profile mirroring that formed during LDL oxidation by activated monocytes in the presence of nitrite. In contrast, oxidized lipid increased with increasing disease severity. These results suggest that two-electron oxidants are primarily responsible for TOH oxidation in the artery wall, and that the extent of TOH oxidation is limited yet substantial lipid oxidation takes place. This study may have important implications regarding antioxidant supplements aimed at preventing LDL oxidation and hence atherogenesis.
Sphingosine-1-Phosphate, a Platelet-Derived Lysophospholipid Mediator, Negatively Regulates Cellular Rac Activity and Cell Migration in Vascular Smooth Muscle Cells
Authors: Ryu Yasuji , Takuwa Noriko , Sugimoto Naotoshi , Sakurada Sotaro , Usui Soichiro , Okamoto Hiroyuki , Matsui Osamu , Takuwa Yoh
Published: July 2002

Previous studies demonstrated that sphingosine-1-phosphate (S1P) induced migration of human umbilical vein endothelial cells (HUVECs) whereas it inhibited that of vascular smooth muscle cells (SMCs). This study explored the molecular mechanisms underlying the contrasting S1P actions on vascular cell motility. In rat and human aortic SMCs, the chemoattractant platelet-derived growth factor B-chain (PDGF) induced rapid 5- to 6-fold increases in the cellular amount of GTP-bound, active form of Rac. S1P did not affect PDGF-stimulated tyrosine phosphorylation of PDGF-β receptor, but strongly inhibited PDGF-induced Rac activation, with a dose-response relationship similar to that for inhibition of PDGF-elicited chemotaxis. Dihydrosphingosine-1-phosphate, which is a weaker agonist for the S1P receptors, but not an inactive ligand sphingosine, also inhibited PDGF-stimulated chemotaxis and Rac activation although to lesser extents compared with S1P, suggesting that negative regulation by S1P of both chemotaxis and Rac was a receptor-mediated process. In contrast, S1P by itself stimulated Rac activity in HUVECs. Among the five S1P receptor isoforms, SMCs prominently expressed Edg-5 mRNA, whereas HUVECs expressed abundant Edg-1 mRNA but lacked detectable expression of Edg-5 mRNA. Adenovirus-mediated expression of a dominant-negative form of either Rac or Cdc42, but not RhoA, markedly attenuated chemotaxis of SMCs and HUVECs toward PDGF and S1P, respectively. Overexpression of Edg-1 in SMCs and Edg-5 in HUVECs reduced S1P-induced inhibition and stimulation, respectively, of Rac activity and migration. These results together indicate that Edg isoform-specific, negative or positive regulation of cellular Rac activity is critically involved in S1P-mediated bimodal regulation of cell motility in SMCs and HUVECs.
Autocrine Stimulation of Cardiac Na
+
-Ca
2+
Exchanger Currents by Endogenous Endothelin Released by Angiotensin II
Authors: Aiello Ernesto A. , Villa-Abrille María C. , Cingolani Horacio E.
Published: July 2002

The goal of the present study was to evaluate the effects of Ang II on the current produced by the Na
+
-Ca
2+
exchanger (
I
NCX
) working in the reverse mode and the possible autocrine role played by the release of endothelin (ET) in these actions.
I
NCX
was studied in isolation in cat cardiac myocytes. Angiotensin II (Ang II) (100 nmol/L) increased
I
NCX
at potentials higher than 0 mV (at +60 mV: 2.07±0.22 pA/pF in control versus 2.73±0.22 pA/pF in Ang II, n=9;
P
<0.05). The increase in
I
NCX
induced by Ang II was prevented by the treatment of the cells with the unspecific blocker of the ET receptors, TAK 044 (1 μmol/L) (at +60 mV: 2.15±0.27 pA/pF in control versus 2.01±0.26 pA/pF in Ang II, n=5, NS). These results show, for the first time, that the effect of Ang II on
I
NCX
is the result of the autocrine actions of ET released by the octapeptide.
Cyclic AMP Raises Intracellular Ca
2+
in Human Megakaryocytes Independent of Protein Kinase A
Authors: den Dekker Els , Heemskerk Johan W.M. , Gorter Gertie , van der Vuurst Hans , Donath José , Kroner Christine , Mikoshiba Katsuhiko , Akkerman Jan-Willem N.
Published: July 2002

The immature megakaryoblastic cell line MEG-01 responds to iloprost with an increase in cytosolic Ca
2+
and cAMP. The Ca
2+
response is almost absent in CHRF-288-11 cells, but cAMP formation is preserved in this more mature megakaryoblastic cell line. Also, in human hematopoietic stem cells, iloprost induces a Ca
2+
response and cAMP formation. The Ca
2+
response is downregulated during megakaryocytopoiesis, but cAMP formation remains unchanged. The Ca
2+
increase may be caused by cAMP-mediated inhibition of Ca
2+
sequestration, because it is (1) independent of Ca
2+
entry; (2) mimicked by forskolin, an activator of adenylyl cyclase, and isobutylmethylxanthine, an inhibitor of phosphodiesterases; and (3) preserved in the presence of inhibitors of protein kinase A and inositol-1,4,5-triphosphate receptors. The small GTPase Rap1 has been implicated in the control of Ca
2+
sequestration. Indeed, Rap1 activation parallels the iloprost- and forskolin-induced Ca
2+
increase and is unaffected by the calcium chelator 1,2-bis(2-aminophenoxy)ethane-
N
,
N
,
N
′,
N
′,-tetraacetic acid-AM. These findings reveal a novel mechanism for elevating cytosolic Ca
2+
by cAMP, possibly via GTP-Rap1.
Inhibition of Platelet-Collagen Interaction
Authors: Westerbacka Jukka , Yki-Järvinen Hannele , Turpeinen Anu , Rissanen Aila , Vehkavaara Satu , Syrjälä Martti , Lassila Riitta
Published: July 2002

Insulin resistance is associated with an increased risk of atherothrombotic vascular disease, but the mechanisms are poorly understood. We determined how insulin in vivo regulates platelet activation in nonobese and obese subjects by using methods mimicking thrombus formation. Twelve nonobese (aged 42±2 years, body mass index 24.0±0.4 kg/m
2
) and 14 obese (aged 43±1 years, body mass index 37.2±1.5 kg/m
2
) subjects were studied under euglycemic hyperinsulinemic (3-hour insulin infusion of 1 mU · kg
−1
· min
−1
) conditions. Before and at the end of hyperinsulinemia, the following were determined: (1) platelet-related early hemostasis (shear rate of ≈4000 s
−1
) by platelet function analysis; (2) platelet deposition to collagen during whole-blood perfusion (shear rate of 1600 s
−1
); (3) aggregation responses to collagen, thrombin receptor-activating peptide, ADP, and epinephrine; and (4) platelet cGMP concentrations. Insulin action on glucose metabolism was 69% lower in the obese subjects (1.6±0.2 mg · kg
−1
· min
−1
) than in the nonobese subjects (5.4±0.4 mg · kg
−1
· min
−1
,
P
<0.0001). The in vivo insulin infusion inhibited platelet deposition to collagen from 4.3±0.6×10
6
to 3.5±0.4×10
6
per square centimeter in the nonobese subjects (
P
<0.05) but failed to do so in the obese subjects (5.2±0.8×10
6
versus 5.5±0.7×10
6
per square centimeter,
P
=NS;
P
<0.01 versus nonobese subjects). Epinephrine- and ADP-primed closure times by platelet function analysis were prolonged by insulin in the nonobese but not the obese subjects (
P
<0.05 for between-group difference). In the nonobese subjects, insulin decreased aggregation to all agonists and significantly increased platelet cGMP concentrations (2.5±0.3 versus 3.2±0.5 pmol/10
9
for before versus after insulin, respectively;
P
<0.01). In the obese subjects, insulin did not alter collagen-induced aggregation or cGMP concentrations (1.9±0.2 versus 1.8±0.1 pmol/10
9
for before versus the end of in vivo hyperinsulinemia, respectively;
P
=NS). These data demonstrate that normal in vivo insulin action inhibits platelet interaction with collagen under conditions mimicking thrombus formation and reduces aggregation to several agonists. These platelet-inhibitory actions of insulin are blunted or absent in obese subjects and could provide 1 mechanism linking insulin resistance to atherothrombotic disease.
Folates and Cardiovascular Disease
Authors: Verhaar M.C. , Stroes E. , Rabelink T.J.
Published: July 2002

It is increasingly recognized that folates may play a role in the prevention of cardiovascular disease. Over the last few years, several studies have reported beneficial effects of folates on endothelial function, a surrogate end point for cardiovascular risk. Consistently, observational studies have demonstrated an association between folate levels and cardiovascular morbidity and mortality. The exact mechanisms underlying the ameliorative effects of folates on the endothelium remain to be elucidated. Thus far, most studies have focused on the homocysteine-lowering effects of folates. However, recently, benefits of folates independent of homocysteine lowering have also been reported. Potential mechanisms include antioxidant actions, effects on cofactor availability, or direct interactions with the enzyme endothelial NO synthase. Obviously, beneficial effects of folates on cardiovascular risk would have important clinical and dietary consequences. However, for definite conclusions, the completion of ongoing randomized controlled trials will have to be awaited.
Effect of Angiotensin II Type 1 Receptor Blockade on Cardiac Remodeling in Angiotensin II Type 2 Receptor Null Mice
Authors: Wu Lan , Iwai Masaru , Nakagami Hironori , Chen Rui , Suzuki Jun , Akishita Masahiro , de Gasparo Marc , Horiuchi Masatsugu
Published: July 2002

To clarify the possible involvement of uninhibited angiotensin II (Ang II) type 2 (AT
2
) receptor stimulation in the effects of an Ang II type 1 (AT
1
) receptor blocker, valsartan, we examined the cardiovascular remodeling induced by aortic banding with the use of wild-type (
Agtr2
+) and AT
2
receptor null (
Agtr2
−) mice. Aortic banding caused cardiac hypertrophy in
Agtr2
+ and
Agtr2
− mice to a similar degree 6 weeks after surgery, whereas coronary arterial thickening and perivascular fibrosis were more exaggerated in
Agtr2
− mice. The AT
2
receptor was observed predominantly in the coronary arteries and perivascular region of
Agtr2+
mice. Valsartan at a dose of 1 mg/kg per day, which did not influence systolic blood pressure, suppressed cardiac hypertrophy similarly in both strains. Valsartan inhibited coronary arterial thickening and perivascular fibrosis in both groups; however, the inhibitory effects of valsartan were significantly weaker in
Agtr2
− mice. The inhibitory effects of a nonselective Ang II receptor antagonist, [Sar
1
,Ile
8
]-Ang II, on cardiac hypertrophy, coronary artery thickening, and perivascular fibrosis were not significantly different in
Agtr2
+ and
Agtr2
− mice. These results suggest that the improvement by valsartan of coronary arterial thickening and perivascular fibrosis after pressure overload is caused by uninhibited AT
2
receptor stimulation in addition to AT
1
receptor blockade.
Activated Mast Cells Increase the Level of Endothelin-1 mRNA in Cocultured Endothelial Cells and Degrade the Secreted Peptide
Authors: Metsärinne Kaj P. , Vehmaan-Kreula Pirjo , Kovanen Petri T. , Saijonmaa Outi , Baumann Marc , Wang Yenfeng , Nyman Tuulikki , Fyhrquist Frej Y. , Eklund Kari K.
Published: July 2002

Subendothelial mast cells have been implicated in the pathogenesis of allergic inflammation, in atherosclerosis, and in the regulation of vascular tone. Because endothelin-1 (ET-1) is an important regulator of vascular tone and has also been implicated in the pathogenesis of atherosclerosis, we studied the role of mast cells in the metabolism of endothelial cell-derived ET-1. In mast cell-endothelial cell cocultures, activation of the mast cells with ensuing degranulation was accompanied by the increased expression of ET-1 mRNA in the endothelial cells, yet the immunoreactive ET-1 protein in the coculture medium disappeared almost completely during the 24-hour coculture. Activation of the mast cells with the ensuing degranulation resulted in proteolytic degradation of ET-1 by the 2 neutral proteases, chymase and carboxypeptidase A, of the exocytosed mast cell granules. With synthetic ET-1 and purified mast cell granule enzymes, efficient degradation of ET-1 by chymase and carboxypeptidase A was verified. These in vitro results imply a novel role for mast cell-derived neutral proteases in ET-1 metabolism and suggest that activated subendothelial mast cells are important local regulators of ET-1 metabolism.
Alcohol-Extracted, but Not Intact, Dietary Soy Protein Lowers Lipoprotein(a) Markedly
Authors: Meinertz Hans , Nilausen Karin , Hilden Jørgen
Published: July 2002

We previously found that dietary soy protein produces higher lipoprotein(a) [Lp(a)] plasma concentrations than does casein. This study tested the hypothesis that soy protein contains Lp(a)-raising alcohol-removable components. Twelve normolipidemic women and men consumed, in a crossover design, liquid-formula diets containing casein, soy protein, or alcohol-extracted soy protein. Dietary periods of 32 days were separated by washout periods on self-selected diets. Fasting lipid and Lp(a) levels were measured throughout. Median Lp(a) concentration was >2-fold greater after 28 to 32 days on a soy protein diet than after an extracted soy protein diet (
P
<0.001). Lp(a) concentrations after casein and extracted soy protein diets were virtually identical. Women and men responded similarly. When the switch was made from a self-selected to a soy protein diet, median Lp(a) concentration increased 16% after 1 week (
P
<0.01) and subsequently decreased toward baseline; extracted soy protein and casein diets never exhibited increased median Lp(a) levels, and after 28 to 32 days, these levels were decreased >60% below baseline (
P
<0.001 and
P
<0.01, respectively). Low density lipoprotein cholesterol concentrations were not different after the 3 experimental diets. The data indicate that (1) dietary soy protein can increase Lp(a) concentrations, (2) this effect is eliminated after alcohol extraction, and (3) high Lp(a) concentrations may be markedly reduced by diet.
Impact of Dietary Intervention, Sex, and Apolipoprotein E Phenotype on Tracking of Serum Lipids and Apolipoproteins in 1- to 5-Year-Old Children
Authors: Rask-Nissilä Leena , Jokinen Eero , Viikari Jorma , Tammi Anne , Rönnemaa Tapani , Marniemi Jukka , Salo Pia , Routi Taina , Helenius Hans , Välimäki Ilkka , Simell Olli
Published: July 2002

The effects of dietary intervention, sex, and apolipoprotein E phenotype on tracking of serum lipid values in young children have remained poorly characterized. We investigated these associations in 1062 infants who were randomized into control and intervention groups (n=522 and n=540, respectively) at age 7 months; the intervention group received counseling aimed at maintaining a low-saturated fat, low-cholesterol diet. In 519 children in the control (n=254) and intervention (n=265) groups, serum lipid values were studied annually between 13 months and 5 years of age. In all children, tracking was strongest for the ratio of high density lipoprotein (HDL) cholesterol to total cholesterol; when a 13-month-old child belonged to the lowest quartile of the distribution, the odds ratio for belonging to the same quartile at older ages was 39.0 (95% CI 23.1 to 66.0). Dietary intervention did not influence the tracking of serum lipids. Tracking of HDL cholesterol was stronger in the boys than in the girls (
P
=0.018). Tracking of non-HDL cholesterol and apolipoprotein B in the children with phenotypes E2/3 or E3/3 was stronger than that in the other children (
P
=0.031 and
P
=0.014, respectively). In conclusion, the apolipoprotein E phenotype strongly influences tracking of non-HDL cholesterol and apolipoprotein B values in early childhood, whereas dietary intervention had no effect on tracking of any of the lipids. A child’s sex influenced tracking only of HDL cholesterol, with boys showing stronger tracking.
Matrix Metalloproteinase Inhibition Impairs Adipose Tissue Development in Mice
Authors: Lijnen H.R. , Maquoi E. , Hansen L.B. , Van Hoef B. , Frederix L. , Collen D.
Published: July 2002

Abstract—

The effect of galardin, a broad-spectrum matrix metalloproteinase (MMP) inhibitor, was studied in mice kept on a high fat diet (HFD). Five-week-old male wild-type mice were fed the HFD (42% fat) for up to 12 weeks and were daily injected intraperitoneally with the inhibitor (100 mg/kg) or with vehicle. After 12 weeks of the HFD, the body weights of both groups were comparable, but the weight of the isolated subcutaneous (SC) or gonadal (GON) fat deposits was significantly lower in the inhibitor-treated group than in the control group (88±11 versus 251±66 mg, respectively, for SC fat [
P
<0.05]; 90±24 versus 217±30 mg, respectively, for GON fat [
P
<0.02]). The number of adipocytes was somewhat higher and the diameter was somewhat smaller (but not significantly) in adipose tissues of the inhibitor-treated group. Adipose tissue of the inhibitor-treated mice contained more collagen than did that of the vehicle-treated mice (Sirius red–stained area of 42±2.6% versus 22±4.4%, respectively, for SC fat [
P
<0.05]; 21±5.1% versus 4.7±0.92%, respectively, for GON fat [
P
<0.01]); a distinct collagen-rich cap was formed around the inhibitor-treated tissue. In situ zymography with casein- or gelatin-containing gels confirmed a reduced MMP activity in SC and GON adipose tissues of inhibitor-treated mice. Thus, in this model, growth and development of adipose tissue appears to be limited by the formation of a collagen-rich matrix cap around the inhibitor-treated tissue. These data suggest a functional role for MMPs in the development of adipose tissue.
Racial Differences in Coronary Artery Calcification in Older Adults
Authors: Newman Anne B. , Naydeck Barbara L. , Whittle Jeff , Sutton-Tyrrell Kim , Edmundowicz Daniel , Kuller Lewis H.
Published: July 2002

Abstract—

Reports on race-related differences in coronary artery calcium (CAC) are just beginning to emerge and have not been well studied in the elderly. This study was undertaken to assess whether such differences exist and the relationship between CAC and cardiovascular risk factors in a cohort of elderly community-dwelling adults. CAC was measured by using electron-beam tomography in 614 adults (aged 67 to 99 years), of whom 59% were women and 23% were black. The median CAC score was lower in blacks than in whites for men (159 versus 787, respectively;
P
<0.001) and for women (134 versus 233, respectively;
P
=0.02) after adjustment for age, cardiovascular disease, and risk factors for cardiovascular disease, although this difference was stronger and remained significant among men only. Lower CAC scores were also observed in the subgroup of blacks with a history of myocardial infarction. The lower CAC scores in blacks compared with whites observed in this study is consistent with either a lower prevalence of coronary artery disease or a lower extent of calcification of coronary artery disease.
Human Coronary Smooth Muscle Cells Internalize Versican-Modified LDL Through LDL Receptor–Related Protein and LDL Receptors
Authors: Llorente-Cortés Vicenta , Otero-Viñas Marta , Hurt-Camejo Eva , Martínez-González José , Badimon Lina
Published: July 2002

Versican-like proteoglycans are the main component of the intimal extracellular matrix interacting with low density lipoprotein (LDL). The aim of this study has been to investigate the receptors involved in versican-modified LDL uptake by human vascular smooth muscle cells (VSMCs). We have found that versican-LDL interaction leads to the following: (1) monomeric LDL particles that are similar in size and electrophoretic mobility to native LDL but that have a higher capacity to induce intracellular cholesteryl ester (CE) accumulation and (2) fused LDL particles similar in size to those obtained by vortexing. The precipitable fraction of versican-LDL, composed of 50% monomeric and 50% fused LDL particles, induced a dose-response increase in the CE content of VSMCs. Anti–LDL receptor antibody decreased the CE accumulation derived from monomeric LDL particles by 88±3% and that derived from the total precipitable fraction by 45±3%. Inhibition of LDL receptor–related protein expression by antisense oligodeoxynucleotides reduced the CE accumulation derived from the precipitable fraction by 65±2.8%, whereas it did not produce any effect on the CE accumulation derived from monomeric LDL. These results suggest that versican-LDL induces CE accumulation in human VSMCs by the LDL receptor (monomeric particles) and LDL receptor–related protein (fused LDL).