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ABSTRACT: Objective: To elucidate whether the microRNA (miRNA) cluster miR-17-92 contributes to the activated phenotype of rheumatoid arthritis synovial fibroblasts (RASF). Methods: RASF were stimulated with tumor necrosis factor alpha (TNFα? and expression and regulation of the miR-17-92 cluster were studied using quantitative real-time PCR (qPCR) and promoter activity assays. RASF were transfected with single precursor molecules of miRNAs from miR-17-92 and the expression of matrix-degrading enzymes and cytokines was measured by qPCR and enzyme-linked immunosorbent assay. Potential miRNA targets were identified by computational prediction and validated using reporter gene assays and Western blot. The activity of NF-κB signaling was determined by reporter gene assay. Results: We found that TNFα induces the expression of miR-17-92 in RASF in a nuclear factor kappa B (NF-κB)-dependent manner. Transfection of RASF with precursor molecules of single members of miR-17-92 revealed significantly increased expression levels of matrix-degrading enzymes, proinflammatory cytokines and chemokines in pre-miR-18a-transfected RASF. Using reporter gene assays we identified the NF-κB pathway inhibitor TNFα-induced protein 3 (TNFAIP3) as a new target of miR-18a. In consequence, pre-miR-18a-transfected RASF showed stronger activation of NF-κB signaling, both constitutively and in response to TNFα-stimulation. Conclusion: Our data suggest that the miR-17-92-derived miR-18a contributes to cartilage destruction and chronic inflammation in the joint through a positive feedback loop in NF-κB signaling with concomitant upregulation of matrix-degrading enzymes and inflammatory mediators in RASF. © 2012 American College of Rheumatology.
Arthritis & Rheumatism 12/2012; · 7.87 Impact Factor
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Katharina Cima,
James Twiss,
Rudolf Speich,
Stephen P McKenna,
Ekkehard Grünig,
Christian M Kähler,
Nicola Ehlken,
Ursula Treder,
Sigrid R Crawford, Lars C Huber,
Silvia Ulrich
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ABSTRACT: BACKGROUND: Individuals with precapillary pulmonary hypertension (PH) experience severely impaired quality of life. A disease-specific outcome measure for PH, the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) was developed and validated in the UK and subsequently adapted for use in additional countries. The aim of this study was to translate and assess the reliability and validity of the CAMPHOR for German-speaking populations. METHODS: Three main adaptation stages involved; translation (employing bilingual and lay panels), cognitive debriefing interviews with patients and validation (assessment of the adaptation's psychometric properties). The psychometric evaluation included 107 patients with precapillary PH (60 females; age mean (standard deviation) 60 (15) years) from 3 centres in Austria, Germany and Switzerland. RESULTS: No major problems were found with the translation process with most items easily rendered into acceptable German. Participants in the cognitive debriefing interviews found the questionnaires relevant, comprehensive and easy to complete. Psychometric analyses showed that the adaptation was successful. The three CAMPHOR scales (symptoms, activity limitations and quality of life) had excellent test-retest reliability correlations (Symptoms = 0.91; Activity limitations = 0.91; QoL = 0.90) and internal consistency (Symptoms = 0.94; Activity limitations = 0.93; QoL = 0.94). Predicted correlations with the Nottingham Health Profile provided evidence of the construct validity of the CAMPHOR scales. The CAMPHOR adaptation also showed known group validity in its ability to distinguish between participants based on perceived general health, perceived disease severity, oxygen use and NYHA classification. CONCLUSIONS: The CAMPHOR has been shown to be valid and reliable in the German population and is recommend for use in clinical practice.
Health and Quality of Life Outcomes 09/2012; 10(1):110. · 2.11 Impact Factor
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ABSTRACT: BACKGROUND: A low resting heart rate (HR) is prognostically favourable in healthy individuals and in patients with left heart disease. In this study we investigated the impact of HR at diagnosis on long-term outcome in patients with differently classified precapillary pulmonary hypertension (pPH). METHODS: pPH patients diagnosed as pulmonary arterial (PAH) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH) were registered and regularly followed at our centre Baseline characteristics and events defined as either death or lung transplantation were noted. The prognostic value of HR was analysed using Kaplan Meier estimates, live tables and Cox regression. RESULTS: 206 patients with PAH (148) and inoperable CTEPH (58) were included. The median HR was 82 bpm. pPH with a HR below 82 bpm had a significantly longer overall event-free survival (2409 vs.1332 days, p = .000). This advantage was similarly found if PAH and CTEPH were analysed separately. Although a lower HR was associated with a better hemodynamic and functional class, HR was a strong and independent prognostic marker for transplant free survival even if corrected for age, sex, hemodynamics and functional status. CONCLUSION: We show that resting HR at diagnosis is a strong and independent long-term prognostic marker in PAH and CTEPH. Whether reducing HR by pharmacological agents would improve outcome in pPH has to be assessed by future trials with high attention to safety.
Respiratory research 09/2012; 13(1):76. · 3.36 Impact Factor
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ABSTRACT: Martorell hypertensive ischemic leg ulcer (Martorell ulcer) is characterized by distinct alterations in the arteriolar wall of subcutaneous vessels, leading to progressive narrowing of the vascular lumen and increase of vascular resistance. These changes are similar to the alterations observed in pulmonary arterioles in patients with chronic pulmonary hypertension (PH). This study was aimed to assess an association between the two disorders.
In this case-control study, 14 patients with Martorell ulcer were clinically assessed for the presence of pulmonary hypertension using transthoracic Doppler echocardiography. Data from patients were compared to 28 matched hypertensive controls.
Systolic pulmonary arterial pressure (sPAP) in patients with Martorell ulcer was significantly higher than in the control group (33.8 ± 16.9 vs 25.3 ± 6.5 mmHg, p = 0.023); the prevalence of pulmonary hypertension was 31% (5/14) in patients and 7% (2/28) in controls (p = 0.031). No differences were seen in left heart size and function between patients and controls.
This study provides first evidence that subcutaneous arteriolosclerosis, the hallmark of Martorell ulcer, is associated with PH. These findings suggest that patients with Martorell leg ulcer might be at significant risk to develop elevated pulmonary arterial pressure. Patients with leg ulcers who present with dyspnea should be evaluated by echocardiography for the presence of pulmonary hypertension.
Respiratory research 06/2012; 13:45. · 3.36 Impact Factor
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Matthias Brock,
Victor J Samillan,
Michelle Trenkmann,
Colin Schwarzwald,
Silvia Ulrich,
Renate E Gay,
Max Gassmann,
Louise Ostergaard,
Steffen Gay,
Rudolf Speich, Lars C Huber
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ABSTRACT: AimsDysregulation of the bone morphogenetic protein receptor type 2 (BMPR2) is a hallmark feature that has been described in several forms of pulmonary hypertension. We recently identified the microRNA miR-20a within a highly conserved pathway as a regulator of the expression of BMPR2. To address the pathophysiological relevance of this pathway in vivo, we employed antagomiR-20a and investigated whether specific inhibition of miR-20a could restore functional levels of BMPR2 and, in turn, might prevent pulmonary arterial vascular remodelling.Methods and resultsFor specific inhibition of miR-20a, cholesterol-modified RNA oligonucleotides (antagomiR-20a) were synthesized. The experiments in mice were performed by using the hypoxia-induced mouse model for pulmonary hypertension and animal tissues were analysed for right ventricular hypertrophy and pulmonary arterial vascular remodelling. Treatment with antagomiR-20a enhanced the expression levels of BMPR2 in lung tissues; moreover, antagomiR-20a significantly reduced wall thickness and luminal occlusion of small pulmonary arteries and reduced right ventricular hypertrophy. To assess BMPR2 signalling and proliferation, we performed in vitro experiments with human pulmonary arterial smooth muscle cells (HPASMCs). Transfection of HPASMCs with antagomiR-20a resulted in activation of downstream targets of BMPR2 showing increased activation of Id-1 and Id-2. Proliferation of HPASMCs was found to be reduced upon transfection with antagomiR-20a.ConclusionThis is the first report showing that miR-20a can be specifically targeted in an in vivo model for pulmonary hypertension. Our data emphasize that treatment with antagomiR-20a restores functional levels of BMPR2 in pulmonary arteries and prevents the development of vascular remodelling.
European Heart Journal 03/2012; · 10.48 Impact Factor
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ABSTRACT: The acute-phase response is an inflammatory process triggered mainly by the cytokine IL-6. Signaling of IL-6 is transduced by activation of STAT3 (signal transducer and activator of transcription 3), which rapidly induces the production of acute-phase proteins such as haptoglobin and fibrinogen. Another target of the IL-6/STAT3 signal transduction pathway is the microRNA cluster miR-17/92. Here, we investigated the interplay of miR-17/92 and STAT3 signaling and its impact on the acute-phase response in primary human hepatocytes and hepatoma (HepG2) cells. Employing a reporter gene system consisting of STAT3-sensitive promoter sequences, we show that the miR-17/92 cluster member miR-18a enhanced the transcriptional activity of STAT3. IL-6 stimulation experiments in miR-18a-overexpressing hepatocytes and HepG2 cells revealed an augmented acute-phase response indicated by increased expression and secretion of haptoglobin and fibrinogen. This effect was due, at least in part, to repression of PIAS3 (protein inhibitor of activated STAT, 3), a repressor of STAT3 activity, which we identified as a novel direct target of miR-18a. Finally, we demonstrate that the expression of miR-17/92 in primary hepatocytes and HepG2 cells is modulated by IL-6. Our data reveal, for the first time, a microRNA-mediated positive feedback loop of IL-6 signal transduction leading to an enhanced acute-phase response in human hepatocytes.
Journal of Biological Chemistry 09/2011; 286(46):40142-50. · 4.77 Impact Factor
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ABSTRACT: To study the expression, regulation and function of the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in synovial fibroblasts (SF) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA).
SF were obtained from RA and OA patients undergoing joint surgery. Expression levels were assessed by quantitative real-time PCR and western blot. Kinase inhibitors and reporter gene assays were employed to study signalling pathways. Functional analyses included EZH2 overexpression by plasmid transfection and gene silencing by small interfering RNA. Chromatin immunoprecipitation assay was used to analyse histone methylation within distinct promoter regions.
By studying the expression and function of EZH2 in SF the authors found that EZH2 is overexpressed in rheumatoid arthritis synovial fibroblasts (RASF) and further induced by tumour necrosis factor alpha through the nuclear factor kappa B and Jun kinase pathways. As a target gene of EZH2 the authors identified secreted frizzled-related protein 1 (SFRP1), an inhibitor of Wnt signalling, which is associated with the activation of RASF, and show that SFRP1 expression correlates with the occupation of its promoter with activating and silencing histone marks.
These data strongly suggest that the chronic inflammatory environment of the RA joint induces EZH2 and thus might cause changes in the epigenetic programmes of SF.
Annals of the rheumatic diseases 05/2011; 70(8):1482-8. · 8.11 Impact Factor
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ABSTRACT: The serotonin system has repeatedly been associated with the pathogenesis of pulmonary hypertension (PH). Objective: To comparatively analyze plasmatic and intrathrombocytic serotonin levels in arterial and mixed venous blood of patients with PH and unaffected controls to elucidate pulmonary serotonin metabolisms.
Catheters were placed in the radial and pulmonary artery in patients with PH (n = 13) for diagnosis and in age-matched controls (n = 6) undergoing percutaneous closure of the patent foramen ovale. Arterial and mixed venous blood samples were immediately centrifuged to obtain plasma and platelets and thereafter frozen at -20°C. After careful thawing, plasmatic and platelet serotonin levels were determined by ELISA.
PH was classified as arterial in 4 and chronic thromboembolic in 9 patients with a mean pulmonary artery pressure of 37 (interquartile range: 32-43) mm Hg. Platelet serotonin content was significantly lower in the PH patients than in the controls. The mean transpulmonary gradient (arterial-mixed venous) was negative in the PH group and positive in the controls. An inverse correlation was found between the arterial blood platelet serotonin content and pulmonary hemodynamics. Plasmatic serotonin levels did not differ between the PH and control groups.
The lower platelet serotonin concentration in PH patients compared with unaffected controls is an unprecedented finding. The negative transpulmonary platelet serotonin gradient and the strong negative correlation of arterial blood platelet serotonin with pulmonary hemodynamics might indicate increased serotonin uptake in the lungs of PH patients.
Respiration 01/2011; 81(3):211-6. · 2.26 Impact Factor
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ABSTRACT: To the Editor: In their review article, Agnelli and Becattini (July 15 issue)(1) discuss many important topics in acute pulmonary embolism. We would like to highlight the importance of the use of pulmonary magnetic resonance imaging (MRI) in the diagnosis of this condition, since substantial technical developments have been introduced in recent years.(2),(3) Continued improvements include the use of parallel imaging, angiography technique, and pulmonary perfusion,(2)-(4) with the latter showing the most promise for the diagnosis of pulmonary embolism.(3) However, even in protocols without pulmonary perfusion, large studies have shown good results with the use of MRI.(5) Overall, . . .
New England Journal of Medicine 11/2010; 363(20):1973-4; author reply 1974-5. · 53.30 Impact Factor
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ABSTRACT: Smoking is a well-known risk factor for cardiovascular, lung, and many other diseases. Smoking can induce pulmonary arterial hypertension (PAH) in animal models; PAH is common in smokers with COPD and thereby not correlated with the degree of airway obstruction. The impact of tobacco smoke exposure on the development of PAH in humans is not known.
In a case-control study we assessed smoking and secondhand smoke exposure in all patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH) seen at our pulmonary hypertension clinic from 2002 until July 2008. Data from patients with PAH were compared with CTEPH and healthy control subjects from the Swiss Health Survey 2007.
Ninety-one patients with PAH were compared with 64 patients with CTEPH and 18,747 control subjects (women 58, 36, 10,331, respectively). Tobacco smoking was significantly more common in PAH compared with CTEPH and control subjects. This difference could be attributed to men. Patients with PAH also smoked longer and more heavily compared with patients with CTEPH. In addition, secondhand smoke exposure was significantly longer in nonsmokers with PAH compared with control subjects.
Our data indicate that tobacco smoke exposure may be a risk factor for men with PAH. Considering smoking as a risk factor for PAH will have implications in counseling patients and especially their hitherto unaffected relatives. Further research on the pathogenetic role of smoking in PAH is warranted.
Chest 11/2010; 138(5):1086-92. · 5.25 Impact Factor
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European Journal of Intensive Care Medicine 10/2010; 36(10):1793-4. · 5.17 Impact Factor
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Caroline Ospelt,
Joachim C. Mertens,
Astrid Jüngel,
Fabia Brentano,
Hanna Maciejewska‐Rodriguez, Lars C. Huber,
Hossein Hemmatazad,
Thomas Wüest,
Alexander Knuth,
Renate E. Gay,
Beat A. Michel,
Steffen Gay,
Christoph Renner,
Stefan Bauer
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ABSTRACT: Objective
Since fibroblasts in the synovium of patients with rheumatoid arthritis (RA) express the serine proteases fibroblast activation protein (FAP) and dipeptidylpeptidase 4 (DPP-4)/CD26, we undertook the current study to determine the functional role of both enzymes in the invasion of RA synovial fibroblasts (RASFs) into articular cartilage.Methods
Expression of FAP and DPP-4/CD26 by RASFs was analyzed using fluorescence-activated cell sorting and immunocytochemistry. Serine protease activity was measured by cleavage of fluorogenic substrates and inhibited upon treatment with L-glutamyl L-boroproline. The induction and expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in RASFs were detected using real-time polymerase chain reaction. Densitometric measurements of MMPs using immunoblotting confirmed our findings on the messenger RNA level. Stromal cell–derived factor 1 (SDF-1 [CXCL12]), MMP-1, and MMP-3 protein levels were measured using enzyme-linked immunosorbent assay. The impact of FAP and DPP-4/CD26 inhibition on the invasiveness of RASFs was analyzed in the SCID mouse coimplantation model of RA using immunohistochemistry.ResultsInhibition of serine protease activity of FAP and DPP-4/CD26 in vitro led to increased levels of SDF-1 in concert with MMP-1 and MMP-3, which are downstream effectors of SDF-1 signaling. Using the SCID mouse coimplantation model, inhibition of enzymatic activity in vivo significantly promoted invasion of xenotransplanted RASFs into cotransplanted human cartilage. Zones of cartilage resorption were infiltrated by FAP-expressing RASFs and marked by a significantly higher accumulation of MMP-1 and MMP-3, when compared with controls.Conclusion
Our results indicate a central role for the serine protease activity of FAP and DPP-4/CD26 in protecting articular cartilage against invasion by synovial fibroblasts in RA.
Arthritis & Rheumatism 02/2010; 62(5):1224 - 1235. · 7.87 Impact Factor
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ABSTRACT: Idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH) share important pathogenic and clinical features. BMPR2 mutations are important in the pathogenesis of IPAH, but little is known about the genetic background in CTEPH. Objective: To search for mutations and polymorphisms in genes involved in the BMPR2, serotonin and nitric oxide pathways possibly associated with pulmonary and cardiac disorders in IPAH and CTEPH.
In a cohort of Swiss patients with IPAH (n = 16) and CTEPH (n = 16), and in 24 controls with left heart disease without PH, polymorphisms in the BMPR2, 5-HHT, 5-HTR-2A and eNOS genes were analyzed and correlated with various clinical, functional and hemodynamic parameters.
We found a BMPR2 missense mutation in a patient with coronary artery disease (CAD) without PH but no BMPR2 mutations in our collective with late-onset sporadic PH. In patients with polymorphic variants of the BMPR2 gene, the number of blood platelets and oxygen saturation were increased. The c.600A-->C synonymous variant was associated with worse exercise capacity and decreased quality of life in PH. We found no significant differences for any measured parameter according to the eNOS, 5-HTR2A and the 5-HTT polymorphisms, although there was a higher allelic frequency of the 5-HTT long variant in IPAH than in CTEPH and controls.
Our first report of a BMPR2 mutation in a patient with CAD without PH is interesting and warrants further investigation. Our study may reflect the clinical status and genetic background in a typical PH cohort as seen in a single tertiary care referral center.
Respiration 10/2009; 79(4):279-87. · 2.26 Impact Factor
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ABSTRACT: Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly affects the synovial tissues of joints. As in other
autoimmune-related disorders, neither the etiology nor the pathogenesis of RA has as yet been completely unraveled. It is
generally accepted, however, that autoimmune disorders develop through a combination of the individual genetic susceptibility,
environmental factors, and dysregulated immune responses. Genetic predisposition has been described in RA, in particular as
“shared epitope”, a distinct sequence of amino acids within the antigen-presenting peptide groove of the major histocompatibility
complex. Imbalanced immunity is reflected by the production of autoantibodies and the accumulation of reactive helper T cells
within the rheumatoid synovium. In addition, environmental factors have been postulated as disease-modulating agents, including
smoking, nutrition and infectious agents. So far, these factors have been studied almost exclusively as separate agents. However,
gene transcription might be affected by ageing and environmental effects (such as nutrition and infections) — without changes
in the nucleotide sequence of the underlying DNA. These patterns of alterations in the gene expression profiles are called
“epigenetics”. The term epigenetics is used to refer to molecular processes that regulate gene expression patterns but without
changing the DNA nucleotide sequence. These epigenetic changes comprise the post-synthetic methylation of DNA and post-transcriptional
modifications of histones, including methylation, phosphorylation, ubiquitination, sumoylation, biotinlyation and, most importantly,
deacetylation and acetylation. With respect to the complex pathogenesis of rheumatic diseases, the “epigenome” is an emerging
concept that integrates different etiologies and, thus, offers the opportunity for novel therapeutic strategies. Based on
the fact that current therapies have not resulted in an ACR70 above 60% and have never been targeting the activated synovial
fibroblast, novel therapeutic strategies should target the epigenetic pathways of synovial activation in RA.
05/2009: pages 193-206;
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Hossein Hemmatazad,
Hanna Maciejewska Rodrigues,
Britta Maurer,
Fabia Brentano,
Margarita Pileckyte,
Jörg H W Distler,
Renate E Gay,
Beat A Michel,
Steffen Gay, Lars C Huber,
Oliver Distler,
Astrid Jüngel
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ABSTRACT: We have recently shown a significant reduction in cytokine-induced transcription of type I collagen and fibronectin in systemic sclerosis (SSc) skin fibroblasts upon treatment with trichostatin A (TSA). Moreover, in a mouse model of fibrosis, TSA prevented the dermal accumulation of extracellular matrix. The purpose of this study was to analyze the silencing of histone deacetylase 7 (HDAC-7) as a possible mechanism by which TSA exerts its antifibrotic function.
Skin fibroblasts from patients with SSc were treated with TSA and/or transforming growth factor beta. Expression of HDACs 1-11, extracellular matrix proteins, connective tissue growth factor (CTGF), and intercellular adhesion molecule 1 (ICAM-1) was analyzed by real-time polymerase chain reaction, Western blotting, and the Sircol collagen assay. HDAC-7 was silenced using small interfering RNA.
SSc fibroblasts did not show a specific pattern of expression of HDACs. TSA significantly inhibited the expression of HDAC-7, whereas HDAC-3 was up-regulated. Silencing of HDAC-7 decreased the constitutive and cytokine-induced production of type I and type III collagen, but not fibronectin, as TSA had done. Most interestingly, TSA induced the expression of CTGF and ICAM-1, while silencing of HDAC-7 had no effect on their expression.
Silencing of HDAC-7 appears to be not only as effective as TSA, but also a more specific target for the treatment of SSc, because it does not up-regulate the expression of profibrotic molecules such as ICAM-1 and CTGF. This observation may lead to the development of more specific and less toxic targeted therapies for SSc.
Arthritis & Rheumatism 05/2009; 60(5):1519-29. · 7.87 Impact Factor
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ABSTRACT: Dysregulated expression of bone morphogenetic protein receptor type II (BMPR2) is a pathogenetic hallmark of pulmonary hypertension. Downregulation of BMPR2 protein but not mRNA has been observed in multiple animal models mimicking the disease, indicating a posttranscriptional mechanism of regulation. Because microRNAs (miRNAs) regulate gene expression mainly through inhibition of target gene translation, we hypothesized that miRNAs may play a role in the modulation of BMPR2. Performing a computational algorithm on the BMPR2 gene, several miRNAs encoded by the miRNA cluster 17/92 (miR-17/92) were retrieved as potential regulators. Ectopic overexpression of miR-17/92 resulted in a strong reduction of the BMPR2 protein, and a reporter gene system showed that BMPR2 is directly targeted by miR-17-5p and miR-20a. By stimulation experiments, we found that the miR-17/92 cluster is modulated by interleukin (IL)-6, a cytokine involved in the pathogenesis of pulmonary hypertension. Because IL-6 signaling is mainly mediated by STAT3 (signal transducer and activator of transcription 3), the expression of STAT3 was knocked down by small interfering RNA, which abolished the IL-6-mediated expression of miR-17/92. Consistent with these data, we found a highly conserved STAT3-binding site in the promoter region of the miR-17/92 gene (C13orf25). Promoter studies confirmed that IL-6 enhances transcription of C13orf25 through this distinct region. Finally, we showed that persistent activation of STAT3 leads to repressed protein expression of BMPR2. Taken together, we describe here a novel STAT3-miR-17/92-BMPR2 pathway, thus providing a mechanistic explanation for the loss of BMPR2 in the development of pulmonary hypertension.
Circulation Research 05/2009; 104(10):1184-91. · 9.49 Impact Factor
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ABSTRACT: Caveolin-1 is a regulator of both intracellular calcium homeostasis and endothelial nitric oxide synthase and may play a pathogenetic role in pulmonary hypertension. In the present study, we aimed to investigate the correlations between pulmonary hemodynamics and vessel morphology including the expression of Caveolin-1 in pulmonary arterioles from patients with chronic obstructive pulmonary disease (COPD) who underwent lung-volume reduction surgery. Staining and subsequent analysis was performed on paraffin-embedded lung tissue from COPD patients (n = 12). Pulmonary arteries with an external diameter of 100-500microm were analysed. Immunhistochemistry with antibodies against caveolin-1 was performed and intensity was assessed. Morphometric data were obtained by using computer-assisted imaging software. The findings were quantified and correlated to hemodynamic data obtained by right-heart catheterization. In COPD patients with pulmonary hypertension (n = 5), the expression of caveolin-1 within the medial smooth muscle cell layer was found to be increased, whereas the intimal caveolin-1 was more prominently expressed in COPD patients with normal pulmonary pressures (n = 7). The ratio between these expression patterns was positively correlated to the mean pulmonary artery pressure. Similar findings were observed for the ratio between intimal and medial thickness as well as for the expression of smooth muscle actin (SMA).Taken together, the expression of caveolin-1 within medial smooth muscle cells of pulmonary arteries in patients with COPD is associated with pulmonary hypertension. Our results thus emphasize a potential novel player in the pathogenesis of COPD-associated pulmonary hypertension.
The Open Respiratory Medicine Journal 02/2009; 3:73-8.
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ABSTRACT: Low bone mineral density (BMD) is common in chronic lung diseases and associated with reduced quality of life. Little is known about BMD in pulmonary hypertension (PH).
Steroid-naïve patients with PH (n=34; 19 idiopathic, 15 chronic thromboembolic) had BMD measured by DXA at the time of diagnostic right heart catheterization. Exercise capacity, quality of life and various parameters related to PH severity and bone metabolism were also assessed. 24 patients with left heart failure (LHF) were similarly assessed as controls.
The prevalence of osteopenia was high both in PH (80%) and in controls with LHF (75%). Low BMD was associated with lean body mass, age, lower BMI, impaired exercise capacity and in PH with higher pulmonary vascular resistance. Serum parathyroid hormone (PTH) was elevated and considerably higher in PH than in LHF (above normal, in 55 vs 29%). Secondary hyperparathyroidism was not related to impaired renal function but possibly to low vitamin D status.
Osteopenia is common in PH and in chronically ill patients with LHF. Osteopenia is associated with known risk factors but in PH also with disease severity. Preventive measures in an increasingly chronic ill PH population should be considered. Secondary hyperparathyroidism is highly prevalent in PH and might contribute to bone and possibly pulmonary vascular disease. Whether adequate vitamin D substitution could prevent low BMD in PH remains to be determined.
The Open Respiratory Medicine Journal 02/2009; 3:53-60.
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Serena Guiducci,
Jörg H W Distler,
Astrid Jüngel,
Dörte Huscher, Lars C Huber,
Beat A Michel,
Renate E Gay,
David S Pisetsky,
Steffen Gay,
Marco Matucci-Cerinic,
Oliver Distler
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ABSTRACT: Microparticles are small, membrane-coated vesicles that can serve as novel signaling structures between cells. The aim of the present study was to analyze the profile of microparticles in the blood of patients with systemic sclerosis (SSc; scleroderma) and healthy controls.
The study population consisted of 37 patients with SSc and 15 healthy subjects of comparable sex and age. Microparticles were isolated from plasma by high-speed differential centrifugation. Microparticles were stained with monoclonal antibodies against cell type-specific markers and were quantified by fluorescence-activated cell sorting analyses.
The total number of microparticles was strongly increased in patients with SSc compared with healthy controls (mean +/- SEM 88.0 +/- 4.8 x 10(5) microparticles/ml plasma versus 42.3 +/- 9.4 x 10(5) microparticles/ml plasma; P < 0.001). Similarly, significant increases were found for microparticles derived from platelets, endothelial cells, monocytes, and T cells, reflecting the activation of these cells in SSc. Platelets were the most common source of microparticles in the blood of patients with SSc (66.9 +/- 5.2% of all microparticles) and healthy donors, followed by microparticles derived from endothelial cells (8.8 +/- 0.9% in SSc patients). The modified Rodnan skin thickness score (MRSS) was inversely correlated with the total number of microparticles. Furthermore, patients with cutaneous ulcers showed a significantly lower total number of microparticles. In multivariate analysis, an additive model of age, C-reactive protein, MRSS, and subtype of disease accounted for 55% of the variability of the total microparticle count (r = 0.744).
The number of microparticles from different cellular sources is increased in the blood of SSc patients. Considering their role as important mediators of intercellular communication, microparticles could be a novel link between activated cellular compartments in the pathogenesis of SSc.
Arthritis & Rheumatism 10/2008; 58(9):2845-53. · 7.87 Impact Factor
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ABSTRACT: Operative joint replacement to treat disabling joint conditions secondary to degenerative and inflammatory arthritides has become one of the most efficacious and cost-effective procedures to relieve pain and restore joint function. However, prosthetic implants are not built to last forever and osteolysis and aseptic loosening has been associated with prosthetic arthroplasties since their introduction. The functional life of a synthetic joint is influenced by many factors including the material of the implant, operation procedures and the surgeon involved, as well as patient-related factors. Although promising developments have been achieved in this field, more than 10% of all implants still have to undergo operative revision within 15 years after the initial operation. Failure due to sepsis, fractures and dislocations has become rare; premature loosening of implants on the other hand is becoming much more important. Prosthetic loosening without concurrent infection or trauma is called aseptic loosening. It is generally accepted that small particles ("wear debris") and activated macrophages play a key role in aseptic loosening. The pathophysiology of this condition, however, is still not very well characterized. In this article, we review the molecular mechanisms and signal pathways that were unravelled as responsible factors for loosening orthopaedic implants. Finally, we discuss possible novel strategies for future therapeutic approaches.
Biomedizinische Technik 02/2008; 53(3):93-103. · 0.86 Impact Factor
