Biomedical subjects

N Marx

Publications and source records attributed to N Marx.

At least 19 recordsLinked to original sources

PubMed2006

[Pharmacotherapy of diabetes mellitus type 2. From the glucocentric tradition towards cardiovascular risk management].

Patients with diabetes type 2 are not directly endangered by dysglycemia but they suffer vascular complications. The diabetic patient with existing cardiovascular disease has a particularly high risk for further cardiovascular complications and therefore requires specific attention. This is not only due to the hyperglycemia, but due to the coexistence of further cardiovascular risk factors, such as hypertension, dyslidemia, visceral fat accumulation, chronic inflammation and coagulopathy, also clinically described as the metabolic syndrome. These patients need an intense and multi-modal therapeutic approach, not only for improvement of glycemic control. Also other vascular risk factors should be handled aggressively, such as blood pressure, coagulopathy and dyslipidemia. Recent studies--as STENO 2--indicate that a multi-modal and aggressive approach in diabetic patients can markedly improve their prognosis. Therefore, the current practice of a glucocentric approach should be changed towards a more vascular approach.

Cardiovascular Diseases↗

PubMed2006

Endotheliotropic elephant herpes virus (EEHV) infection. The first PCR-confirmed fatal case in Asia.

Since 1995, 4 suspected cases of Endotheliotropic Elephant Herpes Virus (EEHV) infection, i.e. based on clinical presentation, have occurred in Asia without resulting in epidemic outbreaks as expected. In order to confirm the presence of EEHV on the continent of Asia, viral DNA particles from liver samples of a wild-caught 3-year-old elephant found dead at a Cambodian elephant sanctuary and clinically diagnosed with EEHV, were PCR processed using known EEHV strain primers. The presence of EEHV viral nucleic acids was confirmed and the nucleic acids had a 99% sequence similarity to the U.S.A strain (gene bank locus: AF117265) and 97% sequence similarity to the European strain (gene bank locus: AF354746) assigning this case to the EEHV-1 cluster. More than the confirmation of EEHV on the continent of Asia, is the phylogenic relationship to the USA and European strains with no corresponding contact or transport of USA or European elephants to Asia. Thus, this brings many of the traditional theories into question. Although almost forgotten, this disease is still ramped in captive elephant populations worldwide and continues to devastate particularly the neonatal and weaning-age population. Special attention and continued research are needed specifically in the area of basic virology and epidemiology.

Animals↗

PubMed2005

Reference values of NT-proBNP serum concentrations in the umbilical cord blood and in healthy neonates and children.

BACKGROUND: N-terminal brain natriuretic peptide (NT-proBNP) is a neurohormonal substance secreted mainly by the cardiac myocytes of the left ventricle and to a less degree of the left atrium. The releasing mechanism is induced by an increased wall stress on the base of volume or pressure load of the ventricle. The physiologic actions of BNP are prohibition of the sympathetic activity, vasodilatation, natriuresis, diureses and inhibition of the renin-angiotensin system. Because of its high sensitivity and specifity in relation to the left ventricular incompetence, BNP as well as NTproBNP are well accepted markers of ventricular dysfunction. It was the aim of the study to establish reference values of NT-proBNP serum concentrations throughout childhood, in particular in the newborn age group. METHODS: In a cross sectional study, serum NT-proBNP concentrations were measured by an ElectroChemiLuminescenceImmunoAssay ("ECLIA" Roche) in the umbilical cord blood of 62 healthy full-term neonates and in 222 healthy probands from birth up to the age of 18 years. RESULTS: The concentration of NT-proBNP in the cord blood samples ranged from 281 to 2595 pg/ml (mean: 818 pg/ml). There was a significant increase in the first days of life followed by a rapid decrease during the first year and a further gradual decrease throughout infancy; beyond the 10(th) year of age normal adult values were approached. CONCLUSIONS: The knowledge of the normal range of plasma NT-proBNP levels in healthy subjects during childhood serves as a non-invasive marker for differentiation of pathologic conditions such as acute myocarditis, hypertrophic or dilated cardiomyopathy, tachyarrhythmias and pulmonary hypertension.

Adolescent↗

PubMed2005

Frequent infection of Hylobates pileatus (pileated gibbon) with species-associated variants of hepatitis B virus in Cambodia.

As well as being distributed widely in human populations, hepatitis B virus (HBV) infections occur frequently in chimpanzee, gibbon and other ape populations in sub-Saharan Africa and South-East Asia. To investigate the frequency and genetic relationships of HBV infecting gibbons in Cambodia, pileated gibbons (Hylobates pileatus) that were originally wild-caught were screened for surface antigen. Twelve of 26 (46 %) were positive, of which 11 were positive for HBV DNA. Phylogenetic analysis of complete genome sequences revealed two distinct genetic groups in the gibbon/orangutan clade. Three were similar to previously described variants infecting H. pileatus in Thailand and eight formed a distinct clade, potentially representing distinct strains of HBV circulating in geographically separated populations in South-East Asia. Because of the ability of HBV to cross species barriers, large reservoirs of infection in gibbons may hamper ongoing attempts at permanent eradication of HBV infection from human populations in South-East Asia through immunization.

Animals↗

PubMed2004

Value of the proximal flow convergence method for quantification of the regurgitant volume in mitral regurgitation Influence of the mechanism of regurgitation, the imaging of the flow convergence region, and different calculation modalities.

UNLABELLED: The purpose of this study was to evaluate whether the underlying mechanism of mitral regurgitation influences the reliability of the proximal flow con- vergence method to assess the regurgitant volume. Furthermore, the mode of imaging the flow convergence region and different correction algorithms for calculation of the regurgitant volume were compared. METHODS: Regurgitant volume was assessed in 45 patients (age 61+/-13 years) with organic (n=19) and functional (n=26) mitral regurgitation by the proximal flow convergence method for aliasing velocities between 14 and 64 cm/s using two-dimensional color Doppler imaging. Different correction and calculation algorithms were compared. In addition, regurgitant volume was determined using color Doppler M-mode for an aliasing velocity of 28 cm/s. The quantitative Doppler method was used as reference. RESULTS: In organic mitral regurgitation correlation coefficients (mean differences) between the proximal flow convergence method and the reference method were 0.25-0.43/ 0.58-0.67 (46-111 ml/15-17 ml) before/after geometric correction of the regurgitant volume for the aliasing velocities investigated. The correlation coefficient (mean difference) using color Doppler M-mode imaging was 0.68 (85 ml). The corresponding values in functional mitral regurgitation were 0.74-0.88/0.74-0.88 (-5-8 ml/-7-5 ml) for two-dimensional color Doppler and 0.88 (-1 ml) for M-mode imaging. CONCLUSIONS: The regurgitant volume was overestimated by the proximal flow convergence method in organic mitral regurgitation irrespective of the application of different correction algorithms or the use of color Doppler M-mode. A sufficiently reliable determination of the regurgitant volume by the proximal flow convergence method was possible in functional mitral regurgitation. In that case a simplified calculation of the regurgitant volume based on the proximal flow convergence method was feasible.

Adult↗

PubMed2003

Pulmonary hemodynamics in obstructive sleep apnea: frequency and causes of pulmonary hypertension.

The association between nocturnal apneas and transient pulmonary hypertension (PHT) has been well documented. However, there is controversy over the frequency and pathophysiological mechanisms of daytime pulmonary hypertension in patients with obstructive sleep apnea (OSAS). The present study sought to evaluate frequency and mechanisms of pulmonary hypertension in patients with OSAS. It included 49 consecutive patients with polysomnographically proven OSAS without pathological lung function testing. All patients performed daytime measurements of pulmonary hemodynamics at rest and during exercise (50-75W). Six patients (12%) had resting PHT mean pulmonary of artery pressure (PAPM) of >20 mmHg), whereas 39 patients (80%) showed PHT during exercise (PAPM >30 mmHg). Multiple regression analysis revealed 3 independent contributing factors for mean pulmonary artery pressure during exercise (PAPMmax): body mass index, age and total lung capacity % of predicted. Twenty-five of the 39 patients with pathologically high PAPMmax (64%) showed elevated pulmonary capillary wedge pressures (PCWPmax > 20 mmHg), whereas no patient had elevated pulmonary vascular resistance (PVRmax > 120 dynes x s x cm(-5)). In conclusion, daytime PHT during exercise is frequently seen in patients with OSAS and normal lung function testing and is mainly caused by abnormally high PCWP, whereas PVR seems to play a minor role.

Adult↗

PubMed2003

Inhibition of MMP-9 expression by PPARgamma activators in human bronchial epithelial cells.

BACKGROUND: The release of matrix degrading enzymes such as matrix metalloproteinase 9 (MMP-9) from bronchial epithelial cells is critically involved in airway wall remodelling in chronic inflammatory processes of the respiratory system. MMP-9 expression is induced by inflammatory mediators such as tumour necrosis factor (TNF)-alpha, but to date nothing is known about the mechanisms of inhibition of MMP-9 expression in these cells. METHODS: A study was undertaken to examine whether activators of the nuclear transcription factor peroxisome proliferator activated receptor gamma (PPARgamma) might modulate MMP-9 expression in two different bronchial epithelial cell lines. RESULTS: PPARgamma was expressed and was functionally active in NL20 and BEAS cells. Activation of PPARgamma by rosiglitazone or pioglitazone significantly reduced TNF-alpha and PMA induced MMP-9 gelatinolytic activity in a concentration dependent manner in both cell lines, but did not alter the expression of tissue inhibitor of MMPs type 1 (TIMP-1), the local inhibitor of MMP-9. Northern blot analysis revealed a decrease in MMP-9 mRNA expression following treatment with PPARgamma which resulted from the inhibition of NF-kappaB activation in these cells, as determined by transient transfection assays and electromobility shift assays. CONCLUSION: Activation of PPARgamma in human bronchial epithelial cells limits the expression of matrix degrading MMP-9. This might have therapeutic applications in chronic inflammatory processes of the respiratory system.

Blotting, Northern↗

PubMed2001

PPARalpha activators inhibit tissue factor expression and activity in human monocytes.

BACKGROUND: Tissue factor (TF), expressed on the surface of monocytes and macrophages in human atherosclerotic lesions, acts as the major procoagulant initiating thrombus formation in acute coronary syndromes. Peroxisome proliferator-activated receptor-alpha (PPARalpha), a nuclear receptor family member, regulates gene expression in response to certain fatty acids and fibric acid derivatives. Given that some of these substances reduce TF activity in patients, we tested whether PPARalpha activators limit TF responses in human monocytic cells. METHODS AND RESULTS: Pretreatment of freshly isolated human monocytes or monocyte-derived macrophages with PPARalpha activators WY14643 and eicosatetraynoic acid (ETYA) led to reduced lipopolysaccharide (LPS)-induced TF activity in a concentration-dependent manner (maximal reduction to 43+/-8% with 250 micromol/L WY14643 [P:<0.05, n=5] and to 42+/-12% with 30 micromol/L ETYA [P:>0.05, n=3]). Two different PPARgamma activators (15-deoxy(_Delta12,14)-prostaglandin J(2) and BRL49653) lacked similar effects. WY14643 also decreased tumor necrosis factor-alpha protein expression in supernatants of LPS-stimulated human monocytes. Pretreatment of monocytes with WY14643 inhibited LPS-induced TF protein and mRNA expression without altering mRNA half-life. Transient transfection assays of a human TF promoter construct in THP-1 cells revealed WY14643 inhibition of LPS-induced promoter activity, which appeared to be mediated through the inhibition of nuclear factor-kappaB but not to be due to reduced nuclear factor-kappaB binding. CONCLUSIONS: PPARalpha activators can reduce TF expression and activity in human monocytes/macrophages and thus potentially reduce the thrombogenicity of atherosclerotic lesions. These data provide new insight into how PPARalpha-activating fibric acid derivatives and certain fatty acids might influence atherothrombosis in patients with vascular disease.

5,8,11,14-Eicosatetraynoic Acid↗

PubMed2001

[Peroxisome proliferator-activated receptors (PPARs) in the vessel wall: new regulators of gene expression in vascular cells].

Peroxisome proliferator-activated receptor alpha and gamma (PPAR alpha, PPAR gamma) are nuclear transcription factors regulating gene expression in response to their ligands. Initially, PPARs were identified as regulators of gene expression in lipid metabolism and adipogenesis, but recent work has demonstrated PPAR expression in vascular cells and suggests antiinflammatory properties in the vasculature. Since PPAR alpha activators include lipid-lowering fibric acid derivatives and since PPAR gamma can be activated by antidiabetic thiazolidinediones, activation of these receptors might be an intriguing tool to influence atherogenesis in patients with vascular disease. However, there is also evidence that PPAR activators might furnish lesion development under certain circumstances. The following review will focus on these aspects of potential anti- or proatherogenic effects in the vessel wall and discuss potential clinical implications of these findings.

Animals↗

PubMed2001

Peroxisome proliferator-activated receptors (PPARs) and their role in the vessel wall: possible mediators of cardiovascular risk?

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that regulate gene expression in response to activation by specific ligands including insulin sensitizing thiazolidinedione and lipid-lowering fibrates. Recent work has identified PPARalpha and PPARgamma expression in vascular cells and established a role for these receptors in the regulation of genes relevant to atherogenesis. The following review will focus on the role of PPAR activation in the vasculature and discuss the potential clinical implications of these findings.

Arteriosclerosis↗

PubMed2000

Peroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells.

Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear hormone receptor superfamily originally shown to play an important role in adipocyte differentiation and glucose homeostasis, is now known to regulate inflammatory responses. Given the importance of endothelial cell (EC)-derived chemokines in regulating leukocyte function and trafficking, we studied the effects of PPARgamma ligands on the expression of chemokines induced in ECs by the Th1 cytokine IFN-gamma. Treatment of ECs with PPARgamma activators significantly inhibited IFN-gamma-induced mRNA and protein expression of the CXC chemokines IFN-inducible protein of 10 kDa (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha-chemoattractant (I-TAC), whereas expression of the CC chemokine monocyte chemoattractant protein-1 was not altered. PPARgamma activators decreased IFN-inducible protein of 10 kDa promoter activity and inhibited protein binding to the two NF-kappaB sites but not to the IFN-stimulated response element ISRE site. Furthermore, PPARgamma ligands inhibited the release of chemotactic activity for CXC chemokine receptor 3 (CXCR3)-transfected lymphocytes from IFN-gamma-stimulated ECs. These data suggest that anti-diabetic PPARgamma activators might attenuate the recruitment of activated T cells at sites of Th1-mediated inflammation.

Chemokine CXCL10↗

PubMed1999

PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells.

BACKGROUND: Adhesion molecule expression on the endothelial cell (EC) surface is critical for leukocyte recruitment to atherosclerotic lesions. Better understanding of transcriptional regulation of adhesion molecules in ECs may provide important insight into plaque formation. Peroxisome proliferator-activated receptor-alpha (PPARalpha), a member of the nuclear receptor family, regulates gene expression in response to certain fatty acids and fibric acid derivatives. The present study investigated PPARalpha expression in human ECs and their regulation of vascular cell adhesion molecule-1 (VCAM-1). METHODS AND RESULTS: Immunohistochemistry revealed that human carotid artery ECs express PPARalpha. Pretreatment of cultured human ECs with the PPARalpha activators fenofibrate or WY14643 inhibited TNF-alpha-induced VCAM-1 in a time- and concentration-dependent manner, an effect not seen with PPARgamma activators. Both PPARalpha activators decreased cytokine-induced VCAM-1 mRNA expression without altering its mRNA half-life. Transient transfection of deletional VCAM-1 promoter constructs and electrophoretic mobility shift assays suggest that fenofibrate inhibits VCAM-1 transcription in part by inhibiting NF-kappaB. Finally, PPARalpha activators significantly reduced adhesion of U937 cells to cultured human ECs. CONCLUSIONS: Human ECs express PPARalpha, a potentially important regulator of atherogenesis through its transcriptional control of VCAM-1 gene expression. Such findings also have implications regarding the clinical use of lipid-lowering agents, like fibric acids, which can activate PPARalpha.

Anticholesteremic Agents↗

PubMed1999

PPARgamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease.

Plasminogen activator inhibitor type-1 (PAI-1) is a major physiological inhibitor of fibrinolysis, with its plasma levels correlating with the risk for myocardial infarction and venous thrombosis. The regulation of PAI-1 transcription by endothelial cells (ECs), a major source of PAI-1, remains incompletely understood. Adipocytes also produce PAI-1, suggesting possible common regulatory pathways between adipocytes and ECs. Peroxisomal proliferator-activated receptor-gamma (PPAR)gamma is a ligand-activated transcription factor that regulates gene expression in response to various mediators such as 15-deoxy-Delta12, 14-prostaglandin J2 (15d-PGJ2) and oxidized linoleic acid (9- and 13-HODE). The present study tested the hypotheses that human ECs express PPARgamma and that this transcriptional activator regulates PAI-1 expression in this cell type. We found that human ECs contain both PPARgamma mRNA and protein. Immunohistochemistry of human carotid arteries also revealed the presence of PPARgamma in ECs. Bovine ECs transfected with a PPAR response element (PPRE)-luciferase construct responded to stimulation by the PPARgamma agonist 15d-PGJ2 in a concentration-dependent manner, suggesting a functional PPARgamma in ECs. Treatment of human ECs with 15d-PGJ2, 9(S)-HODE, or 13(S)-HODE augmented PAI-1 mRNA and protein expression, whereas multiple PPARalpha activators did not change PAI-1 levels. Introduction of increasing amounts of a PPARgamma expression construct in human fibroblasts enhanced PAI-1 secretion from these cells in proportion to the amount of transfected DNA. Thus, ECs express functionally active PPARgamma that regulates PAI-1 expression in ECs. Our results establish a role for PPARgamma in the regulation of EC gene expression, with important implications for the clinical links between obesity and atherosclerosis.

Adipose Tissue↗

PubMed1998

Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells.

Migration of vascular smooth muscle cells (VSMCs) plays an important role in atherogenesis and restenosis after arterial interventions. The expression of matrix metalloproteinases (MMPs), particularly MMP-9, contributes to VSMC migration. This process requires degradation of basal laminae and other components of the arterial extracellular matrix. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor family, regulate gene expression after activation by various ligands. Recent studies have suggested opposing effects of PPAR gamma (PPARgamma) activation on atherogenesis. The present study tested the hypotheses that human VSMCs express PPAR alpha (PPARalpha) and PPARgamma and that PPAR agonists in VSMCs modulate MMP-9 expression and activity, as well as VSMC migration. Human VSMCs expressed PPARalpha and PPARgamma mRNA and protein. Treatment of VSMCs with the PPARgamma ligands troglitazone and the naturally occurring 15-deoxy-Delta12, 14-prostaglandin J2 (15d-PGJ2) decreased phorbol 12-myristate 13-acetate-induced MMP-9 mRNA and protein levels, as well as MMP-9 gelatinolytic activity in the supernatants in a concentration-dependent manner. Six different PPARalpha activators lacked such effects. Addition of prostaglandin F2alpha, known to limit PPARgamma activity, diminished the MMP-9 inhibition seen with either troglitazone or 15d-PGJ2, further implicating PPARgamma in these effects. Finally, troglitazone and 15d-PGJ2 inhibited the platelet-derived growth factor-BB-induced migration of VSMCs in vitro in a concentration-dependent manner. PPARgamma activation may regulate VSMC migration and expression and activity of MMP-9. Thus, PPARgamma activation in VSMCs, via the antidiabetic agent troglitazone or naturally occurring ligands, may act to counterbalance other potentially proatherosclerotic PPARgamma effects.

Becaplermin↗

PubMed1998

Enhancement of monocyte procoagulant activity by adhesion on vascular smooth muscle cells and intercellular adhesion molecule-1-transfected Chinese hamster ovary cells.

BACKGROUND: Plaque erosion is a frequent finding in sudden death due to coronary thrombosis. The present study sought to investigate whether monocyte adhesion to human aortic vascular smooth muscle cells (VSMCs) induces procoagulant activity (PCA) and whether this could be mediated by intercellular adhesion molecule-1 (ICAM-1). METHODS AND RESULTS: We incubated mononuclear cells (MNCs) with VSMCs and ICAM-1-transfected Chinese hamster ovary (CHO) cells, investigated monocyte tissue factor (TF) mRNA expression by Northern blot analysis and TF protein expression by ELISA, and measured PCA. Incubation of MNCs with VSMCs for 6 hours increased PCA from 0.7+/-0.1 to 166.0+/-37.9 mU/105 cells (P=0.007), which could be inhibited in a dose-dependent manner by the addition of blocking anti-ICAM-1 monoclonal antibodies. Prestimulation of VSMCs with interleukin-1beta enhanced surface ICAM-1 expression significantly but did not induce PCA in VSMCs. Incubation of MNCs with prestimulated VSMCs led to a further increase in PCA to 239.9+/-27.9 mU/10(5) cells (P=0.02 compared with incubation with unstimulated VSMCs). Incubation of MNCs with VSMCs enhanced TF mRNA after 2 hours and significantly increased TF protein content after 6 hours. Incubation of purified monocytes with ICAM-1-transfected CHO cells increased PCA from 1.2+/-0.2 to 81.9+/-3.3 mU/10(5) cells (P<0.001 compared with incubation with untransfected CHO cells) after 6 hours. This effect could be inhibited significantly by the addition of blocking anti-CD18, anti-CD11b, or anti-CD11c monoclonal antibodies. Similar results were obtained for MNCs. CONCLUSIONS: Monocyte adhesion to VSMCs induces TF mRNA and protein expression and monocyte PCA, which is regulated by beta2-integrin-mediated monocyte adhesion to ICAM-1 on VSMCs.

Animals↗

PubMed1998

Effect of proteasome inhibitors on monocytic IkappaB-alpha and -beta depletion, NF-kappaB activation, and cytokine production.

We investigated the effect of proteasome inhibitors on the lipopolysaccharide (LPS)-induced expression of several monocytic cytokines, which may be dependent on the transcription factor, nuclear factor-kappaB (NF-kappaB). Exposure of human monocytic THP-1 cells to ALLN and Mu873 prevented the LPS-induced degradation of IkappaB-alpha and -beta, as did the more potent proteasome inhibitor, PSI, whereas several calpain inhibitors were ineffective. This was accompanied by the inhibition of nuclear NF-kappaB binding activity and NF-kappaB transcriptional activation. At the mRNA level, the inhibitors blocked the expression of tumor necrosis factor (TNF) and interleukin-1beta (IL-1beta), whereas IL-8 remained unaffected by ALLN and was only partially reduced by the highest dose of PSI. The latter effect appears to be due to an increase in IL-8 mRNA stability in the presence of proteasome inhibitors. Furthermore, the production of TNF was efficiently suppressed by ALLN and PSI, less by Mu873, and not at all by calpain inhibitors. In primary human blood monocytes ALLN also prevented the LPS-induced degradation of IkappaB-alpha and -beta, efficiently blocked the production of TNF and, to a lesser extent, IL-1beta, whereas that of IL-8 was not inhibited. The expression of NF-kappaB-dependent monocytic cytokines may be selectively controlled by the proteasome, offering a potential therapeutic target in inflammatory disease.

Cell Line↗

PubMed1998

Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma(PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro.

Mononuclear phagocytes play an important role in atherosclerosis and its sequela plaque rupture in part by their secretion of matrix metalloproteinases (MMPs), including MMP-9. Peroxisomal proliferator-activated receptor gamma (PPARgamma), a transcription factor in the nuclear receptor superfamily, regulates gene expression in response to various activators, including 15-deoxy-delta12,14-prostaglandin J2 and the antidiabetic agent troglitazone. The role of PPARgamma in human atherosclerosis is unexplored. We report here that monocytes/macrophages in human atherosclerotic lesions (n = 12) express immunostainable PPARgamma. Normal artery specimens (n = 6) reveal minimal immunoreactive PPARgamma. Human monocytes and monocyte-derived macrophages cultured for 6 days in 5% human serum expressed PPARgamma mRNA and protein by reverse transcription-polymerase chain reaction and Western blotting, respectively. In addition, PPARgamma mRNA expression in U937 cells increased during phorbol 12-myristate 13 acetate-induced differentiation. Stimulation of PPARgamma with troglitazone or 15-deoxy-delta12,14-prostaglandin J2 in human monocyte-derived macrophages inhibited MMP-9 gelatinolytic activity in a concentration-dependent fashion as revealed by zymography. This inhibition correlates with decreased MMP-9 secretion as determined by Western blotting. Thus, PPARgamma is present in macrophages in human atherosclerotic lesions and may regulate expression and activity of MMP-9, an enzyme implicated in plaque rupture. PPARgamma is likely to be an important regulator of monocyte/macrophage function with relevance for human atherosclerotic disease.

Arteriosclerosis↗

PubMed1997

Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets.

BACKGROUND: Activated platelets tether and activate myeloid leukocytes. To investigate the potential relevance of this mechanism in acute myocardial infarction (AMI), we examined cytokine induction by leukocyte-platelet adhesion and the occurrence of leukocyte-platelet conjugates in patients with AMI. METHODS AND RESULTS: We obtained peripheral venous blood samples in 20 patients with AMI before and daily for 5 days after direct percutaneous transluminal coronary angioplasty (PTCA) and in 20 patients undergoing elective PTCA. Throughout the study period, CD41 immunofluorescence of leukocytes (flow cytometry) revealed increased leukocyte-platelet adhesion in patients with AMI compared with control patients (mean +/- SE of fluorescence [channels] before PTCA: 77 +/- 16 versus 35 +/- 9; P = .003). In vitro, thrombin-stimulated fixed platelets bound to neutrophils and monocytes. Within 2 hours, this resulted in increased mRNA for interleukin (IL),1 beta, IL-8, and monocyte chemoattractant protein (MCP)-1 in unfractionated leukocytes. After 4 hours, IL-1 beta and IL-8 concentration of the cell-free supernatant had increased by 268 +/- 36% and 210 +/- 7%, respectively, and cellular MCP-1 content had increased by 170 +/- 8%. Addition of activated platelets to adherent monocytes had a similar effect and was associated with nuclear factor-kappa B activation. Inhibition of binding by anti-P selectin antibodies reduced the effect of activated platelets on cytokine production. CONCLUSIONS: In patients with AMI, leukocyte-platelet adhesion is increased. Binding of activated platelets induces IL-1 beta, IL-8, and MCP-1 in leukocytes. Our findings suggest that leukocyte-platelet adhesion contributes to the regulation of inflammatory responses in AMI.

Adult↗