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2. 1735O PD-L1 expression on immune cells by SP142 co-localises with dendritic cells and is associated with improved overall survival (OS) with atezolizumab in patients with untreated metastatic urothelial cancer (mUC)

Author

Grande Pulido, E., primary, Galsky, M.D., additional, Van Elzen, R., additional, Banchereau, R., additional, Peterson, M., additional, Sedano, C., additional, Koeppen, H., additional, Li, H., additional, Bamias, A., additional, Arranz Arija, J.A., additional, Kikuchi, E., additional, De Santis, M., additional, Davis, I.D., additional, Mellman, I., additional, Oh, S., additional, Williams, P., additional, Bernhard, S., additional, Lee, C.P., additional, Kockx, M., additional, and Mariathasan, S., additional

Published
2022
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4. Biological soil crusts on the Zielitz tailings pile cover.

Author

Sommer V., Gose N., Karsten U., Kockx M., Schmeisky A., Wolk A., Sommer V., Gose N., Karsten U., Kockx M., Schmeisky A., and Wolk A.

Abstract

The covering of potash tailings piles aims at minimising the rain induced brine formation. At the Zielitz site a new covering technique – the infiltration barrier system (IHS) – was developed. By adding insoluble compounds to the top layer of the tailings the water storage capacity and therefore the evaporation rate is improved. During field trials the growth of various photosynthetic active microorganisms and even small plants could be observed. These biological soil crusts can improve the evaporation rates at the surface, contribute to their stability and in the long term lead to soil formation, which finally facilitates settlement by higher plants. (Authors.), The covering of potash tailings piles aims at minimising the rain induced brine formation. At the Zielitz site a new covering technique – the infiltration barrier system (IHS) – was developed. By adding insoluble compounds to the top layer of the tailings the water storage capacity and therefore the evaporation rate is improved. During field trials the growth of various photosynthetic active microorganisms and even small plants could be observed. These biological soil crusts can improve the evaporation rates at the surface, contribute to their stability and in the long term lead to soil formation, which finally facilitates settlement by higher plants. (Authors.)

Published
2021

6. EGFR fluorescence in situ hybridization assay: guidelines for application to non-small-cell lung cancer

Author

Varella-Garcia, M., Diebold, J., Eberhard, D.A., Geenen, K., Hirschmann, A., Kockx, M., Nagelmeier, I., Ruschoff, J., Schmitt, M., Arbogast, S., and Cappuzzo, F.

Subjects
Lung cancer, Non-small cell -- Diagnosis, Lung cancer, Non-small cell -- Research, Tumor markers -- Identification and classification, Tumor markers -- Research, In situ hybridization -- Usage, In situ hybridization -- Research, Health
Published
2009

10. CtDNA as a predictor of outcome in patients treated with neoadjuvant atezolizumab in muscle invasive urothelial cancer

Author

Powles, T, primary, Szabados, B, additional, Castellano, D, additional, Rodriguez-Vida, A, additional, Valderrama, B, additional, Crabb, S, additional, Van Der Heijden, M, additional, Pous, AF, additional, Prendergast, A, additional, Gravis, G, additional, Herranz, UA, additional, Sharma, S, additional, Ravauld, A, additional, Sethi, H, additional, Zimmerman, B, additional, Aleshin, A, additional, Kockx, M, additional, Banchereau, R, additional, Mariathasan, S, additional, and Assaf, ZJ, additional

Published
2020
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11. Ischemic burden reduction after chronic total occlusion percutaneous coronary intervention related to patient prognosis

Author

Schumacher, S.P, primary, Stuijfzand, W.J, additional, Everaars, H, additional, Van Diemen, P.A, additional, Bom, M.J, additional, De Winter, R.W, additional, Kamperman, L, additional, Kockx, M, additional, Hagen, B.S.H, additional, Raijmakers, P.G, additional, Van De Ven, P.M, additional, Van Rossum, A.C, additional, Opolski, M.P, additional, Nap, A, additional, and Knaapen, P, additional

Published
2020
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20. TRAIL-Expressing Monocyte/Macrophages Are Critical for Reducing Inflammation and Atherosclerosis

Author

Cartland, SP, Genner, SW, Martinez, GJ, Robertson, S, Kockx, M, Lin, RCY, O'Sullivan, JF, Koay, YC, Cholan, PM, Kebede, MA, Murphy, AJ, Masters, S, Bennett, MR, Jessup, W, Kritharides, L, Geczy, C, Patel, S, Kavurma, MM, Cartland, SP, Genner, SW, Martinez, GJ, Robertson, S, Kockx, M, Lin, RCY, O'Sullivan, JF, Koay, YC, Cholan, PM, Kebede, MA, Murphy, AJ, Masters, S, Bennett, MR, Jessup, W, Kritharides, L, Geczy, C, Patel, S, and Kavurma, MM

Abstract

Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.

Published
2019

21. Miscellaneous III

Author

Leal, S. R., Flores, J. M., Rivera, V., Camacho, P., Carnacho, J., Murillc, F., Ulibarrena, M. A., Pardo, N. Sainz, Ballestero, J. J., Boado, V., Vergara, J. C., Iruretagoyena, J. R., Kindlund, A., Ponte, C., Valle, J. M., Cienfuegos, F., Payo, F., Sànchez, D., Palacios, F., Polo, M., Toval, A., Latour, J., Bonastre, J., Giner, J. S., Lòpez-Camps, V., Rodrìguez-Serra, M., Rosado, L., Dobrkovic, L., Georgievska, Lj., Spiroska, V., Borozanov, V., Miletić, B., Srbinovski, L., Canovas, J., Barja, D., Perez, A., Marco, P., Caturla, J., Espasa, A., Lucas, J., Voga, C., Žuran, I., Krivec, B., Skrabl-Močnik, F., Skale, R., Marzollo, P., Sebastiano, P., Benedini, G., Marchini, A., Bianchetti, F., Picchioni, A., Pedersini, G., Paylos, J. M., de Sa, E. Lopez, Codero, B., Martinez, J. M., de la Calzada, C. Saenz, Cordero, B., Barro, S., Ruiz, R., Escudcro, J. Lopez, Sànchez, M., Hluchy, J., Wieczorek, M., Sabin, G. V., Ritz, R., Ledermann, H. P., Follath, F., Alexander, J. -P., Cambier, B., Kockx, M., Missault, L., Vandenbogaerde, J., Taeymans, Y., Van Cauwelaert, Ph., Guadagnucci, A., Vignali, G., Mondello, V., Rutili, A., Mariotti, H., Silla, A., Esteban, M., Alfayate, R., Cabello, R. J., Zhang, Haibo, Vincent, Jaan-Louis, Simeoni, U., Desprez, P., Meyer, P., Fischbach, M., Geisert, J., Sproat, L. J., Inglis, T. J. J., Weiss, M., Birkhahn, A., Mettler, S., Schneider, M., Wernet, P., Lemoine, H., Hulsebos, R. G., Beltman, F. W., Miranda, D. Reis, de Jong, I. J., Haas, J. A., Woittiez, A. J. J., Spannbrucker, N., Braun, P., Kleinschmidt, R., Schulte-Witte, H., Scheuerlen, C., Torrent, R. Lorenzo, Palacios, M. Sànchez, Cremades, J. Diaz, Feo, L. Fajardo, Padròn, P. Caballero, Arrate, D. Guerrero, Romero, D. Gonzàlez, Schneider, F., Lutun, Ph., Runge, I., Launoy, A., Hasselmann, M., Tempe, J. D., Moral, A. R., Tünbay, E., Ulusoy, B., Aksoy, N., Çevik, A., Inci, R., Demir, O., Jinènez Jimènez J., Ortiz Leyba C., Garnacho Montero J., Barros Perez M., Ramila Alarcon F., Flores Cordera J., Gonzalez Menendez E., De La Cruz, C., Criado, A., Diaz, L., Seiz, A., Vidaur, P. L., Fraile, J. R., Crespo, E., Arcalfs, L., Hernàndez-Cardona, J. L., Sempere, M. A., Martin, E., Gutierrez, A., Diez, M., de la Torre, F., Picazo, J., Damaso, D., Mazarrtsa, C. F., Noriega, A. R., Cisterna, R., de la Rosa, M., Mirow, N., Meduri, Gianfranco Umberto, Anglada, M. T., Taurà, P., Fuster, J., Bruix, J., Alvarez, L., Izquierdo, E., and Beltràn, J.

Published
1992
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25. P964Relationships between extent of ischemic burden and changes in absolute myocardial perfusion after chronic total occlusion percutaneous coronary intervention

Author

Schumacher, S P, primary, Kockx, M, additional, Stuijfzand, W J, additional, Driessen, R S, additional, Van Diemen, P A, additional, Bom, M J, additional, Everaars, H, additional, Raijmakers, P G, additional, Boellaard, R, additional, Van Rossum, A C, additional, Opolski, M P, additional, Nap, A, additional, and Knaapen, P, additional

Published
2019
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26. Performance of PD-L1 immunohistochemistry (IHC) assays in unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC): Post-hoc analysis of IMpassion130

Author

Rugo, H.S., primary, Loi, S., additional, Adams, S., additional, Schmid, P., additional, Schneeweiss, A., additional, Barrios, C.H., additional, Iwata, H., additional, Dieras, V.C., additional, Winer, E.P., additional, Kockx, M., additional, Peeters, D., additional, Chui, S.Y., additional, Lin, J.C., additional, Nguyen Duc, A., additional, Viale, G., additional, Molinero, L., additional, and Emens, L.A., additional

Published
2019
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27. P5748Impact of specific crossing techniques in chronic total occlusion percutaneous coronary intervention on recovery of absolute myocardial perfusion

Author

Schumacher, S P, primary, Stuijfzand, W J, additional, Driessen, R S, additional, Van Diemen, P A, additional, Bom, M J, additional, Everaars, H, additional, Kockx, M, additional, Raijmakers, P G, additional, Boellaard, R, additional, Van De Ven, P M, additional, Van Rossum, A C, additional, Opolski, M P, additional, Nap, A, additional, and Knaapen, P, additional

Published
2019
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29. Abstract PD9-08: Breast cancer liver metastases vascularize by vessel co-option, not angiogenesis, and have a desert immune phenotype: A histopathological and gene expression study

Author

Vermeulen, PB, primary, van Dam, P-J, additional, Daelemans, S, additional, Latacz, E, additional, Joye, I, additional, Kockx, M, additional, Dirix, P, additional, Verhoef, K, additional, Grunhagen, D, additional, Huget, P, additional, Van Laere, S, additional, and Dirix, LY, additional

Published
2019
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32. ROS1 (SP384) Immunohistochemistry Inter-Reader Precision Between 12 Pathologists

Author

Newell, A. Hanlon, Liu, W., Bubendorf, L., Buettner, R., Kerr, K., Kockx, M., Kossai, M., Lopez-Rios, F., Marchetti, A., Marondel, I., Nicholson, A., Oz, B., Pauwels, P., Penault-Llorca, F., Rossi, G., Russeler, V., Thunnissen, E., Pate, G., Portier, B., Faure, C., Le, C., Smith, D., Menzl, I., Huang, R., Newell, A. Hanlon, Liu, W., Bubendorf, L., Buettner, R., Kerr, K., Kockx, M., Kossai, M., Lopez-Rios, F., Marchetti, A., Marondel, I., Nicholson, A., Oz, B., Pauwels, P., Penault-Llorca, F., Rossi, G., Russeler, V., Thunnissen, E., Pate, G., Portier, B., Faure, C., Le, C., Smith, D., Menzl, I., and Huang, R.

Published
2018

33. MA26.07 ROS1 (SP384) Immunohistochemistry Inter-Reader Precision Between 12 Pathologists

Author

Hanlon Newell, A., primary, Liu, W., additional, Bubendorf, L., additional, Büttner, R., additional, Kerr, K., additional, Kockx, M., additional, Kossai, M., additional, Lopez-Rios, F., additional, Marchetti, A., additional, Marondel, I., additional, Nicholson, A., additional, Oz, B., additional, Pauwels, P., additional, Penault-Llorca, F., additional, Rossi, G., additional, Rüsseler, V., additional, Thunnissen, E., additional, Pate, G., additional, Portier, B., additional, Faure, C., additional, Le, C., additional, Smith, D., additional, Menzl, I., additional, and Huang, R., additional

Published
2018
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34. Genito-urinary genomics and emerging biomarkers for immunomodulatory cancer treatment

Author

Gevaert, T. (Thomas), Montironi, R. (Rodolfo), Lopez-Beltran, A. (Antonio), Leenders, G.J.H.L. (Geert), Allory, Y. (Yves), De Ridder, D. (Dirk), Claessens, F., Kockx, M. (Mark), Akand, M. (Murat), Joniau, S. (Steven), Netto, G. (George), Libbrecht, L., Gevaert, T. (Thomas), Montironi, R. (Rodolfo), Lopez-Beltran, A. (Antonio), Leenders, G.J.H.L. (Geert), Allory, Y. (Yves), De Ridder, D. (Dirk), Claessens, F., Kockx, M. (Mark), Akand, M. (Murat), Joniau, S. (Steven), Netto, G. (George), and Libbrecht, L.

Abstract

Immunotherapy is gradually becoming a key factor in the therapeutic algorithm for patients with genito-urinary (GU) cancers at different stages of disease. Robust and reliable biomarkers are crucial for an appropriate inclusion of patients in clinical trials and for a reliable patient selection for treatments with immunomodulatory drugs. The increasing knowledge on the genomic landscape of GU cancers supports stratification of patients for targeted therapies. This review focusses on emerging biomarkers and the role of genomics in predicting clinical benefit to immunomodulatory agents in GU cancers. Based on cancer incidences and available data we restricted this overview to bladder, prostate and renal cancer.

Published
2017
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35. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis

Author

Van Dam, P.-J. (Pieter-Jan), Stok, E.P. van der, Teuwen, L.-A. (Laure-Anne), Eynden, G. van den, Illemann, M. (Martin), Frentzas, S. (Sophia), Majeed, A.W. (Ali W.), Eefsen, R.L. (Rikke L.), Coebergh van den Braak, R.R.J. (Robert), Lazaris, A. (Anthoula), Fernandez, M.C. (Maria Celia), Galjart, B. (Boris), Laerum, O.D. (Ole Didrik), Rayes, R. (Roni), Grunhagen, D.J. (Dirk Jan), Van De Paer, M. (Michelle), Sucaet, Y. (Yves), Mudhar, H.S. (Hardeep Singh), Schvimer, M. (Michael), Nyström, H. (Hanna), Kockx, M. (Mark), Bird, N.C. (Nigel), Vidal-Vanaclocha, F. (Fernando), Metrakos, P. (Peter), Simoneau, E. (Eve), Verhoef, C. (Kees), Dirix, L.Y. (Luc), Laere, S.J. (Steven) van, Gao, Z.-H. (Zu-Hua), Brodt, P. (Pnina), Reynolds, A.R. (Andrew R.), Vermeulen, P.B. (Peter), Van Dam, P.-J. (Pieter-Jan), Stok, E.P. van der, Teuwen, L.-A. (Laure-Anne), Eynden, G. van den, Illemann, M. (Martin), Frentzas, S. (Sophia), Majeed, A.W. (Ali W.), Eefsen, R.L. (Rikke L.), Coebergh van den Braak, R.R.J. (Robert), Lazaris, A. (Anthoula), Fernandez, M.C. (Maria Celia), Galjart, B. (Boris), Laerum, O.D. (Ole Didrik), Rayes, R. (Roni), Grunhagen, D.J. (Dirk Jan), Van De Paer, M. (Michelle), Sucaet, Y. (Yves), Mudhar, H.S. (Hardeep Singh), Schvimer, M. (Michael), Nyström, H. (Hanna), Kockx, M. (Mark), Bird, N.C. (Nigel), Vidal-Vanaclocha, F. (Fernando), Metrakos, P. (Peter), Simoneau, E. (Eve), Verhoef, C. (Kees), Dirix, L.Y. (Luc), Laere, S.J. (Steven) van, Gao, Z.-H. (Zu-Hua), Brodt, P. (Pnina), Reynolds, A.R. (Andrew R.), and Vermeulen, P.B. (Peter)

Abstract

Background:Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.Methods:Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.Results:Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).Conclusions:The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.

Published
2017
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37. The inflamed immune phenotype can be induced by systemic treatment in angiogenic colorectal liver metastases in contrast to non-angiogenic liver metastases

Author

Stremitzer, S., primary, Vermeulen, P., additional, Kockx, M., additional, Dirix, L., additional, Graver, S., additional, Scherer, S., additional, Yang, D., additional, Zhang, W., additional, Stift, J., additional, Wrba, F., additional, Gruenberger, T., additional, and Lenz, H-J., additional

Published
2017
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43. Belgian Guidelines for HER2testing in gastric cancer

Author

Jouret-Mourin, A., Hoorens, Anne, Kockx, M., Demetter, Pieter, Van Cutsem, E, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (SLuc) Service d'anatomie pathologique, Pathological Anatomy, and Translational Radiation Oncology and Physics

Subjects
gastro-oesophageal junction cancer, in situ hybridisation, trastuzumab, gastric cancer, HER2, immunohistochemistry, otorhinolaryngologic diseases, skin and connective tissue diseases, health care economics and organizations
Abstract

As HER2 testing in gastric cancer is different from that in breast cancer, the Working Group Molecular Pathology, a section of the Belgian Society of Pathology in collaboration with the Belgian Club of Digestive Pathology, the Belgium Group of Digestive Oncology and the Belgium Society of Medical Oncology, formed a committee to establish Belgian guidelines for HER2 testing in gastric cancer. These guidelines are based on the international recommendations and take the Belgian criteria for reimbursement of trastuzumab into account. The aim of these guidelines is to report the consensus of when and how HER2 testing should be performed in gastric cancer in order to establish strategies for ensuring optimal performance, interpretation and reporting assays.

Published
2011

44. 3017 NSCLC with high PD-L1 expression on tumor cells or tumorinfiltrating immune cells represents distinct cancer subtypes

Author

Schmid, P., primary, Kowanetz, M., additional, Koeppen, H., additional, Zou, W., additional, Wistuba, I., additional, Kockx, M., additional, Kadel, E.E., additional, Chaft, J., additional, Rizvi, N.A., additional, Hirsch, F.R., additional, Smith, D., additional, Miley, N., additional, Leveque, V., additional, Shames, D.S., additional, Sandler, A., additional, Mellman, I., additional, Chen, D.S., additional, Hegde, P.S., additional, and Gettinger, S., additional

Published
2015
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47. Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice

Author

Kanters, E., Pasparakis, M., Gijbels, M.J.J., Vergouwe, M.N., Partouns-Hendriks, I., Fijneman, R.J.A., Clausen, B.E., Forster, I., Kockx, M., Rajewsky, K., Kraal, G., Hofker, M.H., de Winther, M.P.J., Pathologie, Moleculaire Celbiologie, Moleculaire Genetica, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, RS: CARIM School for Cardiovascular Diseases, and Faculteit der Geneeskunde

Subjects
sense organs
Abstract

Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. Kanters E, Pasparakis M, Gijbels MJ, Vergouwe MN, Partouns-Hendriks I, Fijneman RJ, Clausen BE, Forster I, Kockx MM, Rajewsky K, Kraal G, Hofker MH, de Winther MP. Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. Atherosclerosis is now generally accepted as a chronic inflammatory condition. The transcription factor NF-kappaB is a key regulator of inflammation, immune responses, cell survival, and cell proliferation. To investigate the role of NF-kappaB activation in macrophages during atherogenesis, we used LDL receptor-deficient mice with a macrophage-restricted deletion of IkappaB kinase 2 (IKK2), which is essential for NF-kappaB activation by proinflammatory signals. These mice showed increased atherosclerosis as quantified by lesion area measurements. In addition, the lesions were more advanced and showed more necrosis and increased cell number in early lesions. Southern blotting revealed that deletion of IKK2 was approximately 65% in macrophages, coinciding with a reduction of 50% in NF-kappaB activation, as compared with controls. In both groups, the expression of differentiation markers, uptake of bacteria, and endocytosis of modified LDL was similar. Upon stimulation with LPS, production of TNF was reduced by approximately 50% in IKK2-deleted macrophages. Interestingly, we also found a major reduction in the anti-inflammatory cytokine IL-10. Our data show that inhibition of the NF-kappaB pathway in macrophages leads to more severe atherosclerosis in mice, possibly by affecting the pro- and anti-inflammatory balance that controls the development of atherosclerosis.

Published
2003

50. Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-α

Author

Kockx, M., Gervois, P. P., Poulain, P., Derudas, B., Peters, J. M., Gonzalez, F. J., Hans Princen, Kooistra, T., Staels, B., and Gaubius instituut TNO

Subjects
Male, Mice, Knockout, Transcription, Genetic, Fibrinogen, Receptors, Cytoplasmic and Nuclear, Procetofen, Rats, DNA-Binding Proteins, Rats, Sprague-Dawley, Clofibric Acid, Kinetics, Mice, Gene Expression Regulation, Liver, Antilipemic Agents, Peroxisome Proliferators, Clofibrate, RNA, Messenger, Rats, Wistar, Biology, Cells, Cultured, Triglycerides, Transcription Factors
Abstract

Plasma fibrinogen levels have been identified as an important risk factor for cardiovascular diseases. Among the few compounds known to lower circulating fibrinogen levels in humans are certain fibrates. We have studied the regulation of fibrinogen gene expression by fibrates in rodents. Treatment of adult male rats with fenofibrate (0.5% [wt/wt] in the diet) for 7 days decreased hepatic Aα-, Bβ-, and γ-chain mRNA levels to 52% ± 7%, 46% ± 8%, and 81% ± 19% of control values, respectively. In parallel, plasma fibrinogen concentrations were decreased to 63% ± 7% of controls. The suppression of fibrinogen expression was dose-dependent and was already evident after 1 day at the highest dose of fenofibrate tested (0.5% [wt/wt]). Nuclear run-on experiments showed that the decrease in fibrinogen expression after fenofibrate occurred at the transcriptional level, as exemplified for the gene for the Aα-chain. Other fibrates tested showed similar effects on fibrinogen expression and transcription. The effect of fibrates is specific for peroxisome proliferator-activated receptor-α (PPARα) because a high- affinity ligand for PPARγ, the thiazolidinedione BRL 49653, lowered triglyceride levels, but was unable to suppress fibrinogen expression. Direct evidence for the involvement of PPARα in the suppression of fibrinogen by fibrates was obtained using PPARα-null (-/-) mice. Compared with (+/+) mice, plasma fibrinogen levels in (-/-) mice were significantly higher (3.20 ± 0.48 v 2.67 ± 0.42 g/L). Also, hepatic fibrinogen Aα-chain mRNA levels were 25% ± 11% higher in the (-/-) mice. On treatment with 0.2% (wt/wt) fenofibrate, a significant decrease in plasma fibrinogen to 77% ± 10% of control levels and in hepatic fibrinogen Aα-chain mRNA levels to 65% ± 12% of control levels was seen in (+/+) mice, but not in (-/-) mice. These studies show that PPARα regulates basal levels of plasma fibrinogen and establish that fibrate-suppressed expression of fibrinogen in rodents is mediated through PPARα.

Published
1999

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