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E Fleck

Publications and source records attributed to E Fleck.

At least 55 records · Page 3Linked to original sources
PubMed2001

Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease.

OBJECTIVES: We sought to determine whether the cardiac renin-angiotensin system (RAS) is activated in human aortic valve disease depending on left ventricular function, and we analyzed the concomitant regulation of the extracellular matrix components. BACKGROUND: In animal models with pressure or volume load, activation of the cardiac RAS increases fibrosis. In human aortic valve disease, the ventricular collagen protein content is increased, but only scarce data on the activation state of the cardiac RAS and its effects on collagen and fibronectin messenger ribonucleic acid (mRNA) are available. METHODS: In left ventricular biopsies from patients with aortic valve stenosis (AS) and aortic valve regurgitation and from control subjects, we quantitated mRNAs for angiotensin-converting enzyme (ACE), chymase, transforming growth factor-beta1 (TGF-beta1), collagen I, collagen III and fibronectin by reverse-transcription polymerase chain reaction. Proteins were localized by immunohistochemistry; ACE activity was determined by high performance liquid chromatography; and TGF-beta protein by quantitative enzyme immunoassay. RESULTS: Protein, ACE and TGF-beta1 mRNA were significantly increased in patients with AS and AR (1.5- to 2.1-fold) and correlated with each other. The increase occurred also in patients with normal systolic function. Collagen I and III and fibronectin mRNAs were both upregulated about twofold in patients with AS and AR. In AS, collagen and fibronectin mRNA expression levels were positively correlated with left ventricular end-diastolic pressure and inversely with left ventricular ejection fraction (LVEF). CONCLUSIONS: In human hearts, pressure and volume overload increases cardiac ACE and TGF-beta1 in the early stages. This activation of the cardiac RAS may contribute to the observed increase in collagen I and III and fibronectin mRNA expression. The increase in extracellular matrix already exists in patients with a normal LVEF, and it increases with functional impairment.

Aged↗
PubMed2001

Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy.

OBJECTIVES: We studied the clinical and genetic features of hypertrophic cardiomyopathy (HCM) caused by mutations in the myosin-binding protein C gene (MYBPC3) in 110 consecutive, unrelated patients and family members of European descent. BACKGROUND: Mutations in the MYBPC3 gene represent the cause of HCM in approximately 15% of familial cases. MYBPC3 mutations were reported to include mainly nonsense versus missense mutations and to be characterized by a delayed onset and benign clinical course of the disease in Japanese and French families. We investigated the features that characterize MYBPC3 variants in a large, unrelated cohort of consecutive patients. METHODS: The MYBPC3 gene was screened by single-strand conformational polymorphism analysis and sequencing. The clinical phenotypes were analyzed using rest and 24-h electrocardiography, electrophysiology, two-dimensional and Doppler echocardiography and angiography. RESULTS: We identified 13 mutations in the MYBPC3 gene: one nonsense, four missense and three splicing mutations and five small deletions and insertions. Of these, 11 were novel, and two were probably founder mutations. Patients with MYBPC3 mutations presented a broad range of phenotypes. In general, the 16 carriers of protein truncations had a tendency toward earlier disease manifestations (33 +/- 13 vs. 48 +/- 9 years; p = 0.06) and more frequently needed invasive procedures (septal ablation or cardioverter-defibrillator implantation) compared with the 9 carriers of missense mutations or in-frame deletions (12/16 vs. 1/9 patients; p < 0.01). CONCLUSIONS: Multiple mutations, which include missense, nonsense and splicing mutations, as well as small deletions and insertions, occur in the MYBPC3 gene. Protein truncation mutations seem to cause a more severe disease phenotype than missense mutations or in-frame deletions.

Adolescent↗
PubMed2001

Clinical validation of new pacing-sensing configurations for atrial automatic capture verification in pacemakers.

INTRODUCTION: This study evaluated an atrial automatic capture verification scheme based on atrial evoked response (AER). Atrial pacing was between Atip and Can (Atip-Can) using different coupling capacitances (CCs). Independent pairs of sensing electrodes between Aring and Vtip (Aring-Vtip) or between Aring and a separate indifferent electrode (Aring-Indiff) were used to reduce pacing-induced afterpotentials. METHODS AND RESULTS: A custom-made external pacing system was used to perform automatic step-up and step-down pacing (0.1 to 7.1 V at 0.5 msec, step size of 0.1 V) using different CCs (2 or 15 microF). Intracardiac signals from Aring-Indiff and Aring-Vtip were independently recorded and analyzed both in real time and off-line to detect AER. Every paced beat also was visually inspected and compared with surface ECG to verify the captures. With the intracardiac signals properly filtered, AER detection was based on the signal within a window of 12 to 65 msec after the stimulus. Data from 27 patients (4 chronic and 23 acute implantations; age 65.6+/-13.9 years) were analyzed. Bipolar atrial lead measurements using a standard pacing system analyzer were as follows (mean +/- SD): impedance 695+/-227 ohms, P wave amplitude 4.2+/-2.3 mV, slew rate 1.1+/-0.9 V/sec, and pacing threshold at 0.5 msec 1.0+/-0.5 V. The results with CC = 2 microF showed that of 9,500 atrial paced beats, correct capture verification rates were 99.8% (Aring-Indiff) and 99.4% (Aring-Vtip). Similar results were achieved with CC = 15 microF (99.7% and 99.5%, respectively). CONCLUSION: AER can be reliably detected using independent pacing (Atip-Can) and sensing (Aring-Vtip or Aring-Indiff) electrodes. Therefore, atrial automatic capture verification by AER detection is feasible.

Adult↗
PubMed2001

The immediate and long-term effect of optimal balloon angioplasty on the absolute coronary blood flow velocity reserve. A subanalysis of the DEBATE study. Doppler Endpoints Balloon Angioplasty Trial Europe.

BACKGROUND: There are limited data regarding the immediate and long-term effect of balloon angioplasty on the coronary flow reserve evaluated in a multicentre setting. METHODS AND RESULTS: A total of 86 patients with one-vessel disease and normal left ventricular function were analysed before and after optimal balloon angioplasty (diameter stenosis <35%) and at 6-month follow-up. Coronary flow reserve was assessed with a Doppler guide wire. A low coronary flow reserve ( 2.5 (46% vs 23% and 36% vs 16%, respectively; P<0.05) due to a trend towards restenosis (29% vs 16%; P=0.15) or a low coronary flow reserve at follow-up due to persistent elevated baseline blood flow velocity. Patients without restenosis showed a decrease or increase of coronary flow reserve during follow-up, determined by alterations of hyperaemic blood flow velocity. CONCLUSIONS: Patients with an impaired coronary flow reserve directly after optimal balloon angioplasty showed a higher target lesion revascularization rate compared to patients with a coronary flow reserve >2.5. This patient group consists of patients prone to develop restenosis, while other patients are characterized by a persistently low coronary flow reserve, probably secondary to disturbed autoregulation and/or diffuse mild coronary atherosclerosis. Coronary flow reserve alterations in patients without restenosis were related to changes in hyperaemic blood flow velocity, suggesting that this phenomenon relates to epicardial remodelling.

Adult↗
PubMed2001

Is contrast-related vasodilatation after intra-coronary iodixanol and iopromide in vivo endothelium-dependent?

AIMS: Goals of the study were the assessment of the correlation between flow-dependent and contrast-related vasodilatation, comparison of iodixanol to iopromide and evaluation of the impact of plaque on vasodilatation in coronary arteries. METHODS AND RESULTS: A controlled randomized paired cross-over comparison between iodixanol (320mgI.ml(-1)) and iopromide (300mgI.ml(-1)) was performed in 10 consecutive patients. Vessel area (Visions Five-64 F/X intra-vascular ultrasound-catheter, Endosonics and blood flow velocity measurements (0.014inches Doppler guide wire, Cardiometrics were recorded simultaneously at an identical position, at baseline, after i.c. bolus injection of 10ml physiologic saline (flow-dependent vasodilatation), and after application of contrast agent 1 and contrast agent 2 as randomized. The action of iodixanol and iopromide on the vascular wall did not differ and was equal to local flow-dependent vasodilatation induced by a saline bolus (correlation 0.95-- 0.98). The increase in local luminal area after injection of saline, iodixanol and iopromide in morphologically normal vessels (approximately 2.5mm(2)) was absent in atherosclerotic segments. Both contrast agents and saline demonstrated a nearly identical flow increase. CONCLUSION: If iodixanol or iopromide are used as contrast agents, contrast-related vessel area increase in vivo seems to be endothelium-dependent.

Adult↗
PubMed2001

Doxazosin inhibits monocyte chemotactic protein 1-directed migration of human monocytes.

Monocyte chemotactic protein 1 (MCP-1)-directed transendothelial migration of monocytes plays a key role in the early development of atherosclerosis. Migration of monocytes requires degradation of extracellular matrices, a process that involves matrix metalloproteinases (MMP) and tissue inhibitors of MMPs (TIMP). Recent studies suggest that the alpha1-adrenergic receptor antagonist doxazosin (Dox) might have antiatherosclerotic effects, although the underlying mechanisms are poorly understood. The purpose of the present study was to determine the effects of Dox on MCP-1-directed monocyte migration, MMP-9 activity, and TIMP-1 expression. MCP-1 (50 ng/ml) stimulated migration of human peripheral blood monocytes (HPBM) 2.7+/-0.42-fold and THP-1 human monocytes 5.9+/-0.83-fold compared with unstimulated control. Dox inhibited MCP-1-induced migration in a dose-dependent manner, with a maximal reduction at 10 microM of 69.5+/-5.9% in HPBM and 72.2+/-3.2% in THP-1 cells. Dox blocked migration even after pretreatment with phenoxybenzamine, an irreversible alpha1-adrenergic receptor antagonist (HPBM: phenoxybenzamine 1 microM + Dox 10 microM, 71.9+/-2.2% inhibition; THP-1 cells: phenoxybenzamine 1 microM + Dox 10 microM: 78+/-7.7% inhibition), suggesting that the antimigratory activity of Dox is mediated through a novel mechanism unrelated to its blocking of the alpha1-adrenergic receptor. Dox (10 microM) inhibited MMP-9 activity by 67.6+/-10.5%, whereas MMP-9 protein levels were not affected. Also, Dox increased PMA-induced-tissue inhibitor of MMPs-1 (TIMP-1) expression by 134.4+/-6.6%. Dox 10 microM. The present study demonstrates a potential novel antiatherosclerotic action of Dox by blocking MCP-1-directed monocyte migration, which might be partly mediated by inhibition of MMP-9 activity.

Adrenergic alpha-Antagonists↗
PubMed2001

Peroxisome proliferator-activated receptor-gamma ligands inhibit nuclear but not cytosolic extracellular signal-regulated kinase/mitogen-activated protein kinase-regulated steps in vascular smooth muscle cell migration.

Vascular smooth muscle cell (VSMC) migration involves adhesion, locomotion, and invasion regulated by various signaling molecules, among which the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) play a critical role. We have shown that the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands troglitazone and rosiglitazone inhibit VSMC migration downstream of ERK MAPK. The purpose of the current study was to more specifically determine which step(s) in VSMC migration are targeted by inhibition of the ERK MAPK pathway or activation of PPAR-gamma. VSMC adhesion was not affected by the ERK MAPK pathway inhibitor PD98059 or PPAR-gamma ligands. Phosphorylation and activation of myosin light chain kinase (MLCK) play important roles in cell locomotion. Platelet-derived growth factor (PDGF)-induced MLCK phosphorylation (1.7-fold) was completely blocked by PD98059 at 30 microM (p < 0.05), but not by troglitazone or rosiglitazone. PDGF-directed migration (5.8-fold) was inhibited by PD98059 (-88% at 30 microM) and the MLCK inhibitor ML9 (0.1-1 microM, -84% at 1 microM) (all p < 0.05). The transcription factor Ets-1 mediates matrix metalloproteinase induction required for tissue invasion by VSMC. PDGF (20 ng/ml) stimulated an Ets-1 protein expression (14-fold at 60 min) in VSMC, which was inhibited by PD98059 (-72% at 30 microM), troglitazone (-69% at 20 microM), and rosiglitazone (-54% at 10 microM) (all p < 0.05). Immunohistochemistry of rat aortae 2 h after balloon injury showed a dramatic upregulation of Ets-1, which was markedly inhibited in animals that had received troglitazone treatment. In contrast, phosphorylated ERK MAPK was not affected by troglitazone. These data are consistent with PPAR-gamma ligands exerting their anti-migratory effects downstream of ERK MAPK activation by blocking nuclear events, such as Ets-1 expression, required for cell invasion in response to arterial injury.

Animals↗
PubMed2001

Angiotensin II induces migration and Pyk2/paxillin phosphorylation of human monocytes.

Angiotensin (Ang) II has been shown to enhance the development of atherosclerotic lesions. Migration of monocytes is an early critical step in the atherosclerotic process. To elucidate mechanisms by which Ang II promotes atherogenesis, we investigated its effects on human monocyte migration. Ang II induced migration of human peripheral blood monocytes (HPBM) and human THP-1 monocytes at concentrations between 0.01 and 1 micromol/L, with a 3.6+/-0.6-fold induction in HPBM and a 4.8+/-0.9-fold induction in THP-1 cells at 1 micromol/L Ang II (both P<0.01 versus unstimulated cells). Addition of the Ang II receptor type 1 (AT1-R) antagonist losartan (1 to 100 micromol/L) suppressed Ang II-induced migration of HPBM and THP-1 monocytes in a dose-dependent manner, demonstrating an AT1-R-mediated mechanism. Ang II-directed migration was also blocked by the Src kinase inhibitor PP2 (10 micromol/L), by the extracellular-regulated protein kinase (ERK 1/2) inhibitor PD98059 (30 micromol/L), and by the p38-MAPK inhibitor SB203580 (10 micromol/L), indicating that Src, ERK 1/2, and p38 are all involved in Ang II-induced migration of HPBM and human THP-1 monocytes. The proline-rich tyrosine kinase 2 (Pyk2) and paxillin are 2 cytoskeleton-associated proteins involved in cell movement, phosphorylated by Ang II in other cell types, and abundantly expressed in monocytes. Ang II (1 micromol/L) induced Pyk2 and paxillin phosphorylation in human THP-1 monocytes, peaking after 10 minutes for Pyk2 with a 6.7+/-0.9-fold induction and after 2 minutes for paxillin with a 3.2+/-0.4-fold induction. Ang II-induced phosphorylation of both proteins was suppressed by losartan and the Src inhibitor PP2, whereas no effect was observed with PD98059 and SB203580. This study demonstrates a novel proatherogenic action of Ang II on human monocytes by stimulating their migration, through an AT1-R-dependent process, involving signaling through Src, ERK 1/2, and p38. Furthermore, the promigratory actions of Ang II in human monocytes are associated with the phosphorylation of 2 cytoskeleton-associated proteins, Pyk2 and paxillin.

Angiotensin II↗
PubMed2001

Selective expression of the proprotein convertases furin, pc5, and pc7 in proliferating vascular smooth muscle cells of the rat aorta in vitro.

The aim of this study was to investigate whether transformation of quiescent vascular smooth muscle cells (VSMCs) into proliferating secretory cells is accompanied by an expression of processing enzymes that activate de novo-synthesized growth factors. Three enzymes belonging to the family of the kexin/subtilisin-like mammalian proprotein convertases (PCs), furin, PC5, and PC7, were found to be upregulated after balloon denudation in vivo. To determine their importance in these cell processes, we investigated their gene regulation using a short-term organ culture system. After incubation of rat aorta for 4 and 24 hr in serum-free medium, we demonstrated a significant induction of VSMC proliferation. The affected subset of VSMCs, positive for alpha-smooth muscle actin, also expressed proliferating cell nuclear antigen (PCNA). Our results revealed a parallel upregulation of furin, PC5, and PC7 in PCNA-immunolabeled cells. As a substrate model for comparison with PCs we used nerve growth factor (NGF). NGF is known to be activated by PCs. As shown by Northern blotting analysis, NGF mRNA concentration was significantly increased in cultured explants. NGF was released into the culture medium. In conclusion, both PCs and NGF are coordinately modulated on induction of VSMC proliferation.

Animals↗
PubMed2001

Patient information: involving the user group.

A review within an acute hospital trust identified problems with in-house information, including a lack of patient involvement, poor quality print and over-use of technical language. A project was set up to improve the quality of the trust's information leaflets.

Educational Status↗
PubMed2000

[Long-term outcome after coronary emergency intervention].

BACKGROUND AND OBJECTIVE: Coronary angioplasty (CAG) has become an acceptable method of treating an acute coronary syndrome (myocardial infarction [MI] or unstable angina [UA]). It was the aim of this study to determine whether the results of such emergency treatment differed from those after elective CAG. PATIENTS AND METHODS: Results of emergency CAG in 581 patients (aged 60 +/- 11 years; 77% males) admitted to the authors' hospital between July 1994 and December 1996 were compared with those of elective CAG in 2,460 patients (aged 61 +/- 10, admitted during the same period. Follow-up information was obtained after 22.4 +/- 11 months in 93.2% of the patients by examination, written answers to annual questionnaires, data being collected on survival, repeat cardia catheterizations, other interventions, aorto-coronary bypass, occurrence of myocardial infarction, the patients' general state and drugs received. RESULTS: 19 of 517 patients (3.7%) of the group who had undergone elective CAG had died during the follow-up period, compared with 107 of 2436 of the emergency cohort (4.4%; not significant). There were also no significant differences regarding repeat cardiac catheterization, interventions, coronary bypass or re-admission. The proportion of subsequent emergency CAG among all CAGs was 16.8% in the emergency cohort, 8.8% after elective angiography (p < 0.001). CONCLUSION: Coronary angiography performed in patients with an acute coronary syndrome has no prognostic significance regarding mortality and morbidity after the acute phase of the disease.

Aged↗
PubMed2000

Should stimulation site be tailored in the individual heart failure patient?

Right ventricular pacing at various sites and shortened atrioventricular (AV) delay has failed to demonstrate a convincing short-term and long-term improvement of left ventricular function. Left-ventricular-based stimulation offers a new therapeutic option for patients with symptomatic congestive heart failure and conduction disturbances, especially of left bundle-branch block configuration. Left ventricular mechanical improvement seems mainly dependent on the pacing site, in addition to optimizing the AV delay. Predominantly retrospective data suggest that pacing the posterolateral free wall results in the greatest hemodynamic improvement. Based on the evaluation of different pacing sites in 2 patients, we noted that site is of major importance for maximal improvement of left ventricular function, and pacing at a suboptimal site can even deteriorate left ventricular contractility. Moreover, lead technology has advanced rapidly and different areas of the left ventricle can now be reached transvenously for acute and chronic placement. Therefore, ongoing trials will help to identify the optimal pacing site and might indicate whether invasive testing will be required in the future.

Arrhythmias, Cardiac↗
PubMed2000

Improvement of myocardial perfusion reserve early after coronary intervention: assessment with cardiac magnetic resonance imaging.

OBJECTIVES: The purpose of this study was to determine the potential value of magnetic resonance myocardial perfusion in the follow-up of patients after coronary intervention. BACKGROUND: In some patients a residual impairment of myocardial perfusion reserve (MPR) early after successful coronary intervention has been observed. In this study we evaluated an MPR index before and after intervention with magnetic resonance. METHODS: Thirty-five patients with single- and multivessel coronary artery disease were studied before and 24 h after intervention. The signal intensity time curves of the first pass of a gadolinium-diethylene triamine pentacetic acid bolus injected via a central vein catheter were evaluated before and after dipyridamole infusion. The upslope was determined using a linear fit. Myocardial perfusion reserve index was estimated from the alterations of the upslope. RESULTS: The MPR index in segments perfused by the stenotic artery was significantly lower than in the control segments (1.07 +/- 0.24 vs. 2.18 +/- 0.35, p < 0.001) and improved significantly after intervention (1.89 +/- 0.39, p < 0.001) but did not normalize completely (p < 0.01). After intervention the MPR index remained significantly lower in the balloon percutaneous transluminal coronary angioplasty group (1.72 +/- 0.38; n = 13) in comparison with the stent group (1.99 +/- 0.36, n = 18, p < 0.05). In the stent group a complete normalization of the MPR index was found 24 h after stenting. CONCLUSIONS: Magnetic resonance perfusion measurements allow a reliable assessment of MPR index. An improvement of MPR index can be observed after coronary intervention, which is more pronounced after stenting. Magnetic resonance perfusion measurements allow the assessment and may be useful for the follow-up of patients with coronary artery disease after coronary intervention.

Angioplasty, Balloon, Coronary↗
PubMed2000

Lung water, hemodynamics and dyspnea before and after valvuloplasty in mitral stenosis.

UNLABELLED: The investigation was to elucidate the role of the reduction of extravascular pulmonary fluid in the immediate symptomatic improvement and its impact on hemodynamics in patients with mitral stenosis treated by percutaneous transluminal valvuloplasty. METHODS: In a prospective study of 12 patients with severe mitral stenosis extravascular pulmonary fluid volume was determined by a combined dye and thermodilution technique (COLD Z-021(TM) Version 5.x, Pulsion((R))) before and after valvuloplasty. Cardiac output, left atrial pressures, atrial V-waves, diastolic transmitral gradients and their respiratory changes were measured. Dyspnea was assessed by validated questionnaires. RESULTS: Symptomatic improvement correlated (r=0. 808) with a decrease of extravascular lung water, but not with either an increase or a decrease of cardiac output or left atrial filling pressures. The decrease of the lung water index may be predicted from the lung water index before valvuloplasty, the final left atrial mean pressure and the cardiac index prior to intervention. The change of the mean difference between inspiratory and expiratory mitral gradient demonstrated a significant inverse correlation with the change of mean left atrial filling pressures (r=-0.778) and with extravascular lung water after valvuloplasty (r=-0.871). CONCLUSION: There is a complex relationship between left atrial filling pressures, extravascular lung water, respiratory changes of gradients, and dyspnea that need further investigation.

Aged↗
PubMed2000

Changes in surface expression of platelet membrane glycoproteins and progression of heart transplant vasculopathy.

BACKGROUND: Transplant vasculopathy is the main limiting factor of the long-term success of heart transplantation. We sought to establish the role of platelets in the development and progression of transplant vasculopathy. METHODS AND RESULTS: Platelet analysis and intracoronary ultrasound examination were performed in 78 heart transplant recipients. Quantitative intracoronary ultrasound was used to define the severity of disease at baseline (48.8+/-4.5 months after transplantation) and at 1-year follow-up. Platelet activation was assessed with the use of immunological surface markers of activation (ligand-induced binding site 1 [LIBS-1], P-selectin, GPIIb-IIIa) and flow cytometry. We found that LIBS-1 immunoreactivity was significantly increased in patients with diffuse disease when compared with focal transplant disease (median [quartile], 27[14, 64] versus 18[7.9, 47], P=0.04). In a logistic regression model, we found that LIBS-1 was an independent predictor for the presence and progression of diffuse transplant vasculopathy (P=0.04). Patients with enhanced LIBS-1 levels (>75% quartile) had a 3.3-fold increased relative risk (95% CI 1.8 and 18.9, P=0.002) for the presence of diffuse transplant vasculopathy. When a cutoff value of 16.5 for the level of LIBS-1 was used, patients had a 4.8-fold increased relative risk (95% CI 1.9 and 12.5, P<0.01) for the progression of transplant vasculopathy. CONCLUSIONS: Enhanced platelet activation is strongly associated with the development and progression of transplant vasculopathy. Understanding the underlying pathophysiological mechanisms might contribute to the development of treatment strategies to prevent transplant vasculopathy.

Blood Platelets↗
PubMed2000

Peroxisome proliferator-activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes.

Monocyte chemotactic protein-1 (MCP-1)-directed transendothelial migration of monocytes plays a key role in the development of inflammatory diseases. Infiltration of tissues by monocytes requires degradation of extracellular matrices, a process that involves matrix metalloproteinases. We studied the effects of peroxisome proliferator-activated receptor (PPAR) gamma, alpha, and retinoid X receptor alpha (RXRalpha) ligands on MCP-1-directed migration and matrix metalloproteinase expression of a human acute monocytic leukemia cell line (THP-1). PPARgamma ligands attenuated MCP-1-induced migration, with 50% inhibition (IC(50)) at 2.8 microM for troglitazone and 4.8 microM for rosiglitazone. PPARalpha ligands WY-14643 (IC(50): 0.9 microM) and 5,8,11,14-eicosatetranoic acid (IC(50): 9.9 microM), and the potent RXRalpha ligand AGN 4204 (IC(50): 3.6 nM) also blocked monocyte migration. Troglitazone, rosiglitazone, or AGN 4204 inhibited phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 expression. PPARalpha activators WY-14643 and 5,8,11,14-eicosatetraynoic acid, however, had no inhibitory effect. AGN 4204 increased PMA-induced tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) expression, whereas all PPAR ligands showed no effect. All PPAR and RXRalpha ligands blocked chemotaxis of THP-1 monocytes in the absence of a matrix barrier. This study demonstrates that activated PPARs and RXRalpha, block MCP-1-directed monocyte migration, mediated, at least in part, through their effects on matrix metalloproteinase-9 or TIMP-1 production, or chemotaxis.

5,8,11,14-Eicosatetraynoic Acid↗