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1. Exploring the interactions between cardiomyocytes and endothelial cells to induce cardiac revascularization and regeneration

Author

Vuerich, R, primary, Colliva, A, additional, Vodret, S, additional, Volpe, M C, additional, Braga, L, additional, Canarutto, G, additional, Piazza, S, additional, Pedrazzini, T, additional, Chiesa, M, additional, Cauteruccio, M, additional, Ramadan, M, additional, Zentilin, L, additional, Giacca, M, additional, and Zacchigna, S, additional

Published
2024
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3. Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

Author

De Nittis P., Efthymiou S., Sarre A., Guex N., Chrast J., Putoux A., Sultan T., Raza Alvi J., Ur Rahman Z., Zafar F., Rana N., Rahman F., Anwar N., Maqbool S., Zaki M. S., Gleeson J. G., Murphy D., Galehdari H., Shariati G., Mazaheri N., Sedaghat A., Lesca G., Chatron N., Salpietro V., Christoforou M., Houlden H., Simonds W. F., Pedrazzini T., Maroofian R., Reymond A., SYNAPS STUDY GROUP: SYNAPS Study Group: Stanislav Groppa, Blagovesta Marinova Karashova, Wolfgang Nachbauer, Sylvia Boesch, Larissa Arning, Dagmar Timmann, Bru Cormand, Belen Pérez-Dueñas, Jatinder S Goraya, Tipu Sultan, Jun Mine, Daniela Avdjieva, Hadil Kathom, Radka Tincheva, Selina Banu, Mercedes Pineda-Marfa, Pierangelo Veggiotti, Michel D. Ferrari, Arn M. J. M. van den Maagdenberg, Alberto Verrotti, Giangluigi Marseglia, Salvatore Savasta, Mayte García-Silva, Alfons Macaya Ruiz, Barbara Garavaglia, Eugenia Borgione, Simona Portaro, Benigno Monteagudo Sanchez, Richard Boles, Savvas Papacostas, Michail Vikelis, Eleni Zamba Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Shahnaz Ibrahim, Salman Kirmani, Nuzhat Noureen Rana, Osama Atawneh, George Koutsis, Salvatore Mangano, Carmela Scuderi, Giovanna Morello, Tanya Stojkovic, Massimo Zollo, Gali Heimer, Yves A. Dauvilliers, Pasquale Striano, Issam Al-Khawaja, Fuad Al-Mutairi, Hamed Sherifa., University of Lausanne (UNIL), University College of London [London] (UCL), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Children's Hospital [Lahore], Institute of Child Health [Lahore], Children's Hospital [Multan], Institute of Child Health [Multan], National Research Centre - NRC (EGYPT), Howard Hughes Medical Institute (HHMI), Shahid Chamran University of Ahvaz (SCU), Ahvaz Jundishapur University of Medical Sciences (AJUMS), National Institutes of Health [Bethesda] (NIH), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL), Herrada, Anthony, P., De Nitti, S., Efthymiou, A., Sarre, N., Guex, J., Chrast, A., Putoux, T., Sultan, J., Raza Alvi, Z., Ur Rahman, F., Zafar, N., Rana, F., Rahman, N., Anwar, S., Maqbool, M. S., Zaki, J. G., Gleeson, D., Murphy, H., Galehdari, G., Shariati, N., Mazaheri, A., Sedaghat, G., Lesca, N., Chatron, V., Salpietro, M., Christoforou, H., Houlden, W. F., Simond, T., Pedrazzini, R., Maroofian, A., Reymond, STUDY GROUP: SYNAPS Study Group: Stanislav Groppa, Synap, Marinova Karashova, Blagovesta, Nachbauer, Wolfgang, Boesch, Sylvia, Arning, Larissa, Timmann, Dagmar, Cormand, Bru, Pérez-Dueñas, Belen, S Goraya, Jatinder, Sultan, Tipu, Mine, Jun, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Banu, Selina, Pineda-Marfa, Mercede, Veggiotti, Pierangelo, Ferrari, Michel D., van den Maagdenberg, Arn M. J. M., Verrotti, Alberto, Marseglia, Giangluigi, Savasta, Salvatore, García-Silva, Mayte, Macaya Ruiz, Alfon, Garavaglia, Barbara, Borgione, Eugenia, Portaro, Simona, Monteagudo Sanchez, Benigno, Boles, Richard, Papacostas, Savva, Vikelis, Michail, Zamba Papanicolaou, Eleni, Dardiotis, Efthymio, Maqbool, Shazia, Ibrahim, Shahnaz, Kirmani, Salman, Noureen Rana, Nuzhat, Atawneh, Osama, Koutsis, George, Mangano, Salvatore, Scuderi, Carmela, Morello, Giovanna, Stojkovic, Tanya, Zollo, Massimo, Heimer, Gali, Dauvilliers, Yves A., Striano, Pasquale, Al-Khawaja, Issam, Al-Mutairi, Fuad, and Sherifa., Hamed

Subjects
Male, 0301 basic medicine, Developmental Disabilities, Batecs cardíacs, 0302 clinical medicine, Neurodevelopmental disorder, Heart Rate, Medicine, Child, Genetics (clinical), Mice, Knockout, Gnb5-null mouse models, GTP-Binding Protein beta Subunits, Cardiac muscle, Heart, Syndrome, IDDCA, Functional Genomics, Pedigree, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, cardiac conduction anomalies, Gnb5 -null mouse models, GNB5 variants, medicine.anatomical_structure, Child, Preschool, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, medicine.symptom, Signal Transduction, Bradycardia, Cardiac function curve, Gnb5 -null mouse model, medicine.medical_specialty, Adolescent, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Contractility, Young Adult, Brain damage, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, GNB5variants, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Internal medicine, Exome Sequencing, Heart rate, Genetics, Animals, Humans, business.industry, Gene Expression Profiling, Heart beat, Proteins, Cardiac arrhythmia, Arrhythmias, Cardiac, GNB5 variant, medicine.disease, Mice, Inbred C57BL, Autonomic nervous system, 030104 developmental biology, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Lesions cerebrals, cardiac conduction anomalie, business, Proteïnes, 030217 neurology & neurosurgery
Abstract

BackgroundPathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia.MethodsWe used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse.ResultsWe delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5−/− mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/−, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5−/− mice. In contrast, Gnb5−/− mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients.ConclusionsOur data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5−/− mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening.

Published
2020

6. Dissecting the transcriptome in cardiovascular disease.

Author

Robinson, Emma L, Baker, Andrew H, Brittan, Mairi, McCracken, Ian, Condorelli, G, Emanueli, C, Srivastava, P K, Gaetano, C, Thum, T, Vanhaverbeke, M, Angione, C, Heymans, S, Devaux, Y, Pedrazzini, T, Martelli, F, and CA17129, EU-CardioRNA COST Action

Subjects
CARDIOVASCULAR diseases, TRANSCRIPTOMES, NON-coding RNA, LINEAR network coding, CARDIOVASCULAR system
Abstract

The human transcriptome comprises a complex network of coding and non-coding RNAs implicated in a myriad of biological functions. Non-coding RNAs exhibit highly organized spatial and temporal expression patterns and are emerging as critical regulators of differentiation, homeostasis, and pathological states, including in the cardiovascular system. This review defines the current knowledge gaps, unmet methodological needs, and describes the challenges in dissecting and understanding the role and regulation of the non-coding transcriptome in cardiovascular disease. These challenges include poor annotation of the non-coding genome, determination of the cellular distribution of transcripts, assessment of the role of RNA processing and identification of cell-type specific changes in cardiovascular physiology and disease. We highlight similarities and differences in the hurdles associated with the analysis of the non-coding and protein-coding transcriptomes. In addition, we discuss how the lack of consensus and absence of standardized methods affect reproducibility of data. These shortcomings should be defeated in order to make significant scientific progress and foster the development of clinically applicable non-coding RNA-based therapeutic strategies to lessen the burden of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Published
2022
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10. The continuous heart failure spectrum: Moving beyond an ejection fraction classification

Author

Triposkiadis, F. Butler, J. Abboud, F.M. Armstrong, P.W. Adamopoulos, S. Atherton, J.J. Backs, J. Bauersachs, J. Burkhoff, D. Bonow, R.O. Chopra, V.K. De Boer, R.A. De Windt, L. Hamdani, N. Hasenfuss, G. Heymans, S. Hulot, J.-S. Konstam, M. Lee, R.T. Linke, W.A. Lunde, I.G. Lyon, A.R. Maack, C. Mann, D.L. Mebazaa, A. Mentz, R.J. Nihoyannopoulos, P. Papp, Z. Parissis, J. Pedrazzini, T. Rosano, G. Rouleau, J. Seferovic, P.M. Shah, A.M. Starling, R.C. Tocchetti, C.G. Trochu, J.-N. Thum, T. Zannad, F. Brutsaert, D.L. Segers, V.F. De Keulenaer, G.W.

Subjects
cardiovascular system, cardiovascular diseases, circulatory and respiratory physiology
Abstract

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as ‘HFrEF’ (HF with reduced LVEF), ‘HFpEF’ (HF with preserved LVEF), and more recently ‘HFmrEF’ (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone. © The Author(s) 2019.

Published
2019

12. Catalyzing transcriptomics research in cardiovascular disease:the CardioRNA COST Action CA17129

Author

Gomes, C. P. (Clarissa Pedrosa da Costa), Agg, B. (Bence), Andova, A. (Andrejaana), Arslan, S. (Serdal), Baker, A. (Andrew), Bartekova, M. (Monika), Beis, D. (Dimitris), Betsou, F. (Fay), Wettinger, S. B. (Stephanie Bezzina), Bugarski, B. (Branko), Condorelli, G. (Gianluigi), da Silva, G. J. (Gustavo Jose Justo), Danilin, S. (Sabrina), de Gonzalo-Calvo, D. (David), Buil, A. (Alfonso), Carmo-Fonseca, M. (Maria), Enguita, F. J. (Francisco J.), Felekkis, K. (Kyriacos), Ferdinandy, P. (Peter), Gyoengyoesi, M. (Mariann), Hackl, M. (Matthias), Karaduzovic-Hadziabdic, K. (Kanita), Hellemans, J. (Jan), Heymans, S. (Stephane), Hlavackova, M. (Marketa), Hoydal, M. A. (Morten Andre), Jankovic, A. (Aleksandra), Jusic, A. (Amela), Kardassis, D. (Dimitris), Kerkela, R. (Risto), Kuster, G. M. (Gabriela M.), Lakkisto, P. (Paivi), Leszek, P. (Przemyslaw), Lustrek, M. (Mitja), Maegdefessel, L. (Lars), Martelli, F. (Fabio), Novella, S. (Susana), O'Brien, T. (Timothy), Papaneophytou, C. (Christos), Pedrazzini, T. (Thierry), Pinet, F. (Florence), Popescu, O. (Octavian), Potocnjak, I. (Ines), Robinson, E. (Emma), Sasson, S. (Shlomo), Scholz, M. (Markus), Simionescu, M. (Maya), Stoll, M. (Monika), Varga, Z. V. (Zoltan V.), Vinciguerra, M. (Manlio), Xuereb, A. (Angela), Yilmaz, M. B. (Mehmet Birhan), Emanueli, C. (Costanza), Devaux, Y. (Yvan), Gomes, C. P. (Clarissa Pedrosa da Costa), Agg, B. (Bence), Andova, A. (Andrejaana), Arslan, S. (Serdal), Baker, A. (Andrew), Bartekova, M. (Monika), Beis, D. (Dimitris), Betsou, F. (Fay), Wettinger, S. B. (Stephanie Bezzina), Bugarski, B. (Branko), Condorelli, G. (Gianluigi), da Silva, G. J. (Gustavo Jose Justo), Danilin, S. (Sabrina), de Gonzalo-Calvo, D. (David), Buil, A. (Alfonso), Carmo-Fonseca, M. (Maria), Enguita, F. J. (Francisco J.), Felekkis, K. (Kyriacos), Ferdinandy, P. (Peter), Gyoengyoesi, M. (Mariann), Hackl, M. (Matthias), Karaduzovic-Hadziabdic, K. (Kanita), Hellemans, J. (Jan), Heymans, S. (Stephane), Hlavackova, M. (Marketa), Hoydal, M. A. (Morten Andre), Jankovic, A. (Aleksandra), Jusic, A. (Amela), Kardassis, D. (Dimitris), Kerkela, R. (Risto), Kuster, G. M. (Gabriela M.), Lakkisto, P. (Paivi), Leszek, P. (Przemyslaw), Lustrek, M. (Mitja), Maegdefessel, L. (Lars), Martelli, F. (Fabio), Novella, S. (Susana), O'Brien, T. (Timothy), Papaneophytou, C. (Christos), Pedrazzini, T. (Thierry), Pinet, F. (Florence), Popescu, O. (Octavian), Potocnjak, I. (Ines), Robinson, E. (Emma), Sasson, S. (Shlomo), Scholz, M. (Markus), Simionescu, M. (Maya), Stoll, M. (Monika), Varga, Z. V. (Zoltan V.), Vinciguerra, M. (Manlio), Xuereb, A. (Angela), Yilmaz, M. B. (Mehmet Birhan), Emanueli, C. (Costanza), and Devaux, Y. (Yvan)

Abstract

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field. COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).

Published
2019

13. Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway

Author

Zhu, M., Feng, J., Lucchinetti, E., Fischer, G., Xu, L., Pedrazzini, T., Schaub, M C., Zaugg, M., Zhu, M., Feng, J., Lucchinetti, E., Fischer, G., Xu, L., Pedrazzini, T., Schaub, M C., and Zaugg, M.

Abstract

OBJECTIVE: We tested whether ischemic postconditioning (IPostC) is protective in remodeled myocardium. METHODS: Post-myocardial infarct (MI)-remodeled hearts after permanent coronary artery ligation and one kidney one clip (1K1C) hypertensive hearts of male Wistar rats were exposed to 40 min of ischemia followed by 90 min of reperfusion. IPostC was induced by six cycles of 10 s reperfusion interspersed by 10 s of no-flow ischemia. Activation of reperfusion injury salvage kinases was measured using Western blotting and in vitro kinase activity assays. RESULTS: IPostC prevented myocardial damage in both MI-remodeled and 1K1C hearts, as measured by decreased infarct size and lactate dehydrogenase release, and improved function. The reduction in infarct size and the recovery of left ventricular contractility achieved by IPostC was less in 1K1C hearts, but was unchanged in MI-remodeled hearts when compared to healthy hearts. In contrast, the recovery of inotropy was unaffected in 1K1C hearts, but was less in MI-remodeled hearts. Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway with LY294002 abolished the protective effects of IPostC on both disease models and healthy hearts. Western blot analysis in conjunction with in vitro kinase activity assays identified protein kinase B (PKB)/Akt but not p42/p44 extracellular-signal regulated kinase 1/2 (ERK1/2) as the predominant kinase in IPostC-mediated cardioprotection in remodeled hearts. IPostC increased phosphorylation of the PKB/Akt downstream targets eNOS, GSK3beta, and p70S6K in remodeled hearts. CONCLUSION: Our results offer evidence that IPostC mediates cardioprotection in the remodeled rat myocardium primarily via activation of the PI3K-PKB/Akt reperfusion injury salvage kinase pathway

Published
2017

15. Le coeur des ARN non codants - Un long chemin à découvrir [In the heart of noncoding RNA: a long way to go]

Author

Pedrazzini, T.

Subjects
Adult, Animals, Cardiomegaly/genetics, Chromosome Mapping, Gene Amplification/genetics, Gene Regulatory Networks, Heart/embryology, Humans, Myocardial Infarction/genetics, Myocardial Infarction/metabolism, Myocardium/metabolism, RNA, Untranslated/genetics, RNA, Untranslated/metabolism
Abstract

The identification and characterization of long noncoding RNA in a variety of tissues represent major achievements that contribute to our understanding of the molecular mechanisms controlling gene expression. In particular, long noncoding RNA play crucial roles in the epigenetic regulation of the adaptive response to environmental cues via their capacity to target chromatin modifiers to specific locus. In addition, these transcripts have been implicated in controlling splicing, translation and degradation of messenger RNA. Long noncoding RNA have also been shown to act as decoy molecules for microRNA. In the heart, a few long noncoding RNA have been demonstrated to regulate cardiac commitment and differentiation during development. Furthermore, recent findings suggest their involvement as regulators of the pathophysiological response to injury in the adult heart. Their high cellular specificity makes them attractive target molecules for innovative therapies and ideal biomarkers.

Published
2015

16. The promise of enhancer-associated long noncoding RNAs in cardiac regeneration

Author

Ounzain, S. and Pedrazzini, T.

Abstract

Heart failure is a worldwide epidemic and represents a major cause of morbidity and mortality. Current clinical therapies for heart disease prolong survival by protecting the viable muscle, but they are unable to replenish lost cardiomyocytes to restore function. Over the last decade, the notion of promoting cardiac regeneration has engendered considerable research interest. New strategies envisage the transfer of stem cells into the damaged myocardium, the mobilization of cardiac precursor cells, the promotion of cardiomyocyte proliferation in situ and direct reprogramming of non-cardiac cells into electromechanically coupled cardiomyocytes. The molecular and cellular mechanisms underpinning these different regenerative avenues are under the control of integrated transcriptional programs, which are ultimately dependent on epigenomic reprogramming and reorganization of the genome nuclear architecture. Today, it is becoming evident that regulatory noncoding RNAs play fundamental roles in all these aspects of gene regulatory network activity. In particular, thousands of long noncoding RNAs are dynamically expressed across the entire genome during lineage-specific commitment, specialization, and differentiation, as well as during the response to environmental cues. Here, we review this emerging landscape, focusing particularly on a unique class of lncRNA emerging from enhancer sequences, the enhancer-associated lncRNAs, in the context of cardiac regeneration. We propose that characterizing and manipulating these enhancer-associated transcripts could provide a novel approach to awaken the dormant regenerative potential of the adult mammalian heart. Ultimately, this could lead to targeted noncoding RNA-based enhancer therapies to improve effectiveness of current regenerative strategies and provide new avenues for repair.

Published
2015

17. Discovery and functional characterization of cardiovascular long noncoding RNAs

Author

Ounzain, S., Burdet, F., Ibberson, M., and Pedrazzini, T.

Subjects
Cardiovascular System/metabolism, RNA, Long Noncoding/genetics, RNA, Long Noncoding/metabolism
Abstract

Recent advances in sequencing and genomic technologies have resulted in the discovery of thousands of previously unannotated long noncoding RNAs (lncRNAs). However, their function in the cardiovascular system remains elusive. Here we review and discuss considerations for cardiovascular lncRNA discovery, annotation and functional characterization. Although we primarily focus on the heart, the proposed pipeline should foster functional and mechanistic exploration of these transcripts in various cardiovascular pathologies. Moreover, these insights could ultimately lead to novel therapeutic approaches targeting lncRNAs for the amelioration of cardiovascular diseases including heart failure.

Published
2015

18. Activation of N-methyl D-aspartate (NMDA) receptors has no influence on rheological properties of erythrocytes

Author

Reinhart W H, Geissmann-Ott C, Bogdanova A, Krebs T, Felley A, Montessuit C, Tokarska-Schlattner M, Aasum E, Perriard E, Perriard JC, Larsen T, Pedrazzini T, Krek W, University of Zurich, and Reinhart, W H

Subjects
Agonist, Erythrocyte Aggregation, medicine.medical_specialty, Erythrocytes, Physiology, medicine.drug_class, 2720 Hematology, Individuality, Blood Sedimentation, Hematocrit, Receptors, N-Methyl-D-Aspartate, 2705 Cardiology and Cardiovascular Medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, 2737 Physiology (medical), Suspensions, Memantine, Physiology (medical), Internal medicine, Erythrocyte Deformability, medicine, Excitatory Amino Acid Agonists, Humans, Calcium Signaling, Receptor, Homocysteine, 030304 developmental biology, 0303 health sciences, Ion Transport, medicine.diagnostic_test, Viscosity, Hematology, Buffer solution, 1314 Physiology, 10081 Institute of Veterinary Physiology, Homocysteic acid, Shear rate, Endocrinology, chemistry, 030220 oncology & carcinogenesis, NMDA receptor, 570 Life sciences, biology, Cardiology and Cardiovascular Medicine, Shear Strength, Excitatory Amino Acid Antagonists, medicine.drug, circulatory and respiratory physiology
Abstract

Purpose Red blood cells (RBCs) express N-methyl D-aspartate (NMDA) receptors on their surface. We tested if NMDA receptor activation or inhibition had an influence on RBC deformability and aggregability. Methods Heparinized blood was drawn from healthy volunteers and centrifuged. RBCs were washed twice and resuspended with a hematocrit of 30% in a same buffer solution containing 3% dextran 70. Aliquots were prepared: a) control; b) containing 100 μM homocysteic acid (NMDA receptor agonist); c) 100 μM memantine (NMDA receptor inhibitor) and 100 μM homocysteic acid. RBC suspension viscometry (Contraves LS-30) was done at 37 °C with shear rates of 37.6 s(-1) and 0.1 s(-1). RBC aggregability was assessed with a Myrenne aggrometer and sedimentation rate. Results Neither NMDA receptor activation nor inhibition had an influence on biophysical properties of RBCs. RBC suspension viscosity at a shear rate of 37.6 s(-1) was 3.62 ± 0.16, 3.61 ± 0.13, and 3.62 ± 0.16 mPa.s for control, homocysteic acid, and memantine + homocysteic acid, respectively, indicating an unchanged RBC deformability. The RBC aggregability parameters (low shear viscosity, Myrenne aggregometry at stasis (M) and 3 s(-1) (M1), and the sedimentation rate) showed no influence of either memantine and/or homocysteic acid. A large interindividual variability in RBC aggregability was observed. A good correlation was found between M, M1 and sedimentation values, but not with low shear viscosity values. Conclusions An activation or inhibition of NMDA receptors on RBCs has no influence on their deformability and aggregability. RBC aggregability varies largely among individuals, which was consistently detected by the sedimentation rate and the Myrenne aggregometer, but not by low shear viscosity, which should not be used for this purpose.

Published
2011

21. Ageing-related cardiomyocyte functional decline is sex and angiotensin II dependent

Author

Mellor, KM, Curl, CL, Chandramouli, C, Pedrazzini, T, Wendt, IR, Delbridge, LMD, Mellor, KM, Curl, CL, Chandramouli, C, Pedrazzini, T, Wendt, IR, and Delbridge, LMD

Abstract

Clinically, heart failure is an age-dependent pathological phenomenon and displays sex-specific characteristics. The renin-angiotensin system mediates cardiac pathology in heart failure. This study investigated the sexually dimorphic functional effects of ageing combined with angiotensin II (AngII) on cardiac muscle cell function, twitch and Ca(2+)-handling characteristics of isolated cardiomyocytes from young (~13 weeks) and aged (~87 weeks) adult wild type (WT) and AngII-transgenic (TG) mice. We hypothesised that AngII-induced contractile impairment would be exacerbated in aged female cardiomyocytes and linked to Ca(2+)-handling disturbances. AngII-induced cardiomyocyte hypertrophy was evident in young adult mice of both sexes and accentuated by age (aged adult ~21-23 % increases in cell length relative to WT). In female AngII-TG mice, ageing was associated with suppressed cardiomyocyte contractility (% shortening, maximum rate of shortening, maximum rate of relaxation). This was associated with delayed cytosolic Ca(2+) removal during twitch relaxation (Tau ~20 % increase relative to young adult female WT), and myofilament responsiveness to Ca(2+) was maintained. In contrast, aged AngII-TG male cardiomyocytes exhibited peak shortening equivalent to young TG; yet, myofilament Ca(2+) responsiveness was profoundly reduced with ageing. Increased pro-arrhythmogenic spontaneous activity was evident with age and cardiac AngII overexpression in male mice (42-55 % of myocytes) but relatively suppressed in female aged transgenic mice. Female myocytes with elevated AngII appear more susceptible to an age-related contractile deficit, whereas male AngII-TG myocytes preserve contractile function with age but exhibit desensitisation of myofilaments to Ca(2+) and a heightened vulnerability to arrhythmic activity. These findings support the contention that sex-specific therapies are required for the treatment of age-progressive heart failure.

Published
2014

22. S100A1 deficiency results in prolonged ventricular repolarization in response to sympathetic activation

Author

Ackermann, G.E., Domenighetti, A.A., Deten, Alexander, Bonath, I., Marenholz, I., Pedrazzini, T., Erne, P., Heizmann, C.W., University of Zurich, Heizmann, C W, and Publica

Subjects
10036 Medical Clinic, S100A1, 570 Life sciences, biology, 610 Medicine & health, transcriptome profiling, genetically altered mice, 1314 Physiology, 10081 Institute of Veterinary Physiology, QT and ST intervals, 1304 Biophysics
Abstract

S100A1 is a Ca2+-binding protein and predominantly expressed in the heart. We have generated a mouse line of S100A1 deficiency by gene trap mutagenesis to investigate the impact of S100A1 ablation on heart function. Electrocardiogram recordings revealed that after beta-adrenergic stimulation S100A1-deficient mice had prolonged QT, QTc and ST intervals and intraventricular conduction disturbances reminiscent of 2 : 1 bundle branch block. In order to identify genes affected by the loss of S100A1, we profiled the mutant and wild type cardiac transcriptomes by gene array analysis. The expression of several genes functioning to the electrical activity of the heart were found to be significantly altered. Although the default prediction would be that mRNA and protein levels are highly correlated, comprehensive immunoblot analyses of salient up- or down-regulated candidate genes of any cellular network revealed no significant changes on protein level. Taken together, we found that S100A1 deficiency results in cardiac repolarization delay and alternating ventricular conduction defects in response to sympathetic activation accompanied by a significantly different transcriptional regulation.

Published
2008

23. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs

Author

Ounzain, S., primary, Micheletti, R., additional, Beckmann, T., additional, Schroen, B., additional, Alexanian, M., additional, Pezzuto, I., additional, Crippa, S., additional, Nemir, M., additional, Sarre, A., additional, Johnson, R., additional, Dauvillier, J., additional, Burdet, F., additional, Ibberson, M., additional, Guigo, R., additional, Xenarios, I., additional, Heymans, S., additional, and Pedrazzini, T., additional

Published
2014
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25. Stabilised beta-catenin in postnatal ventricular myocardium leads to dilated cardiomyopathy and premature death

Author

Hirschy, A, Croquelois, A, Perriard, E, Schoenauer, R, Agarkova, I, Hoerstrup, S P, Taketo, M M, Pedrazzini, T, Perriard, J-C, Ehler, E, Hirschy, A, Croquelois, A, Perriard, E, Schoenauer, R, Agarkova, I, Hoerstrup, S P, Taketo, M M, Pedrazzini, T, Perriard, J-C, and Ehler, E

Abstract

Beta-catenin is a component of the intercalated disc in cardiomyocytes, but can also be involved in signalling and activation of gene transcription. We wanted to determine how long-term changes in beta-catenin expression levels would affect mature cardiomyocytes. Conditional transgenic mice that either lacked beta-catenin or that expressed a non-degradable form of beta-catenin in the adult ventricle were created. While mice lacking beta-catenin in the ventricle do not have an overt phenotype, mice expressing a non-degradable form develop dilated cardiomyopathy and do not survive beyond 5 months. A detailed analysis could reveal that this phenotype is correlated with a distinct localisation of beta-catenin in adult cardiomyocytes, which cannot be detected in the nucleus, no matter how much protein is present. Our report is the first study that addresses long-term effects of either the absence of beta-catenin or its stabilisation on ventricular cardiomyocytes and it suggests that beta-catenin's role in the nucleus may be of little significance in the healthy adult heart.

Published
2010

26. Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy

Author

Blyszczuk, P, Kania, G, Dieterle, T, Marty, R R, Valaperti, A, Berthonneche, C, Pedrazzini, T, Berger, C T, Dirnhofer, S, Matter, C M, Penninger, J M, Lüscher, T F, Eriksson, U, Blyszczuk, P, Kania, G, Dieterle, T, Marty, R R, Valaperti, A, Berthonneche, C, Pedrazzini, T, Berger, C T, Dirnhofer, S, Matter, C M, Penninger, J M, Lüscher, T F, and Eriksson, U

Abstract

RATIONALE: The myeloid differentiation factor (MyD)88/interleukin (IL)-1 axis activates self-antigen-presenting cells and promotes autoreactive CD4(+) T-cell expansion in experimental autoimmune myocarditis, a mouse model of inflammatory heart disease. OBJECTIVE: The aim of this study was to determine the role of MyD88 and IL-1 in the progression of acute myocarditis to an end-stage heart failure. METHODS AND RESULTS: Using alpha-myosin heavy chain peptide (MyHC-alpha)-loaded, activated dendritic cells, we induced myocarditis in wild-type and MyD88(-/-) mice with similar distributions of heart-infiltrating cell subsets and comparable CD4(+) T-cell responses. Injection of complete Freund's adjuvant (CFA) or MyHC-alpha/CFA into diseased mice promoted cardiac fibrosis, induced ventricular dilation, and impaired heart function in wild-type but not in MyD88(-/-) mice. Experiments with chimeric mice confirmed the bone marrow origin of the fibroblasts replacing inflammatory infiltrates and showed that MyD88 and IL-1 receptor type I signaling on bone marrow-derived cells was critical for development of cardiac fibrosis during progression to heart failure. CONCLUSIONS: Our findings indicate a critical role of MyD88/IL-1 signaling in the bone marrow compartment in postinflammatory cardiac fibrosis and heart failure and point to novel therapeutic strategies against inflammatory cardiomyopathy.

Published
2009

27. Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway

Author

Zhu, M, Feng, J, Lucchinetti, E, Fischer, G, Xu, L, Pedrazzini, T, Schaub, M C, Zaugg, M, Zhu, M, Feng, J, Lucchinetti, E, Fischer, G, Xu, L, Pedrazzini, T, Schaub, M C, and Zaugg, M

Abstract

OBJECTIVE: We tested whether ischemic postconditioning (IPostC) is protective in remodeled myocardium. METHODS: Post-myocardial infarct (MI)-remodeled hearts after permanent coronary artery ligation and one kidney one clip (1K1C) hypertensive hearts of male Wistar rats were exposed to 40 min of ischemia followed by 90 min of reperfusion. IPostC was induced by six cycles of 10 s reperfusion interspersed by 10 s of no-flow ischemia. Activation of reperfusion injury salvage kinases was measured using Western blotting and in vitro kinase activity assays. RESULTS: IPostC prevented myocardial damage in both MI-remodeled and 1K1C hearts, as measured by decreased infarct size and lactate dehydrogenase release, and improved function. The reduction in infarct size and the recovery of left ventricular contractility achieved by IPostC was less in 1K1C hearts, but was unchanged in MI-remodeled hearts when compared to healthy hearts. In contrast, the recovery of inotropy was unaffected in 1K1C hearts, but was less in MI-remodeled hearts. Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway with LY294002 abolished the protective effects of IPostC on both disease models and healthy hearts. Western blot analysis in conjunction with in vitro kinase activity assays identified protein kinase B (PKB)/Akt but not p42/p44 extracellular-signal regulated kinase 1/2 (ERK1/2) as the predominant kinase in IPostC-mediated cardioprotection in remodeled hearts. IPostC increased phosphorylation of the PKB/Akt downstream targets eNOS, GSK3beta, and p70S6K in remodeled hearts. CONCLUSION: Our results offer evidence that IPostC mediates cardioprotection in the remodeled rat myocardium primarily via activation of the PI3K-PKB/Akt reperfusion injury salvage kinase pathway.

Published
2006

28. Deletion of the neuropeptide Y Y1 receptor affects pain sensitivity, neuropeptide transport and expression, and dorsal root ganglion neuron numbers

Author

Shi, T-J S, Dahlström, A, Theodorsson, Elvar, Ceccatelli, S, Decosterd, I, Pedrazzini, T, Hökfelt, T, Shi, T-J S, Dahlström, A, Theodorsson, Elvar, Ceccatelli, S, Decosterd, I, Pedrazzini, T, and Hökfelt, T

Abstract

Neuropeptide Y has been implicated in pain modulation and is substantially up-regulated in dorsal root ganglia after peripheral nerve injury. To identify the role of neuropeptide Y after axotomy, we investigated the behavioral and neurochemical phenotype of neuropeptide Y Y1 receptor knockout mice with focus on dorsal root ganglion neurons and spinal cord. Using a specific antibody Y1 receptor immunoreactivity was found in dorsal root ganglia and in dorsal horn neurons of wild-type, but not knockout mice. The Y1 receptor knockout mice exhibited a pronounced mechanical hypersensitivity. After sciatic nerve axotomy, the deletion of Y1 receptor protected knockout mice from the axotomy-induced loss of dorsal root ganglion neurons seen in wild-type mice. Lower levels of calcitonin gene-related peptide and substance P were identified by immunohistochemistry in dorsal root ganglia and dorsal horn of knockout mice, and the axotomy-induced down-regulation of both calcitonin gene-related peptide and substance P was accentuated in Y1 receptor knockout. However, the transcript levels for calcitonin gene-related peptide and substance P were significantly higher in knockout than in wild-type dorsal root ganglia ipsilateral to the axotomy, while more calcitonin gene-related peptide- and substance P-like immunoreactivity accumulated proximal and distal to a crush of the sciatic nerve. These results indicate that the deletion of the Y1 receptor causes increased release and compensatory increased synthesis of calcitonin gene-related peptide and substance P in dorsal root ganglion neurons. Together, these findings suggest that, after peripheral nerve injury, neuropeptide Y, via its Y1 receptor receptor, plays a key role in cell survival as well as in transport and synthesis of the excitatory dorsal horn messengers calcitonin gene-related peptide and substance P and thus may contribute to pain hypersensitivity. © 2006 IBRO.

Published
2006
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29. Abstracts

Author

Dunet, V., primary, Dabiri, A., additional, Allenbach, G., additional, Goyeneche Achigar, A., additional, Waeber, B., additional, Feihl, F., additional, Heinzer, R., additional, Prior, J. O., additional, Van Velzen, J. E., additional, Schuijf, J. D., additional, De Graaf, F. R., additional, De Graaf, M. A., additional, Schalij, M. J., additional, Kroft, L. J., additional, De Roos, A., additional, Jukema, J. W., additional, Van Der Wall, E. E., additional, Bax, J. J., additional, Lankinen, E., additional, Saraste, A., additional, Noponen, T., additional, Klen, R., additional, Teras, M., additional, Kokki, T., additional, Kajander, S., additional, Pietila, M., additional, Ukkonen, H., additional, Knuuti, J., additional, Pazhenkottil, A. P., additional, Nkoulou, R. N., additional, Ghadri, J. R., additional, Herzog, B. A., additional, Buechel, R. R., additional, Kuest, S. M., additional, Wolfrum, M., additional, Gaemperli, O., additional, Husmann, L., additional, Kaufmann, P. A., additional, Andreini, D., additional, Pontone, G., additional, Mushtaq, S., additional, Antonioli, L., additional, Bertella, E., additional, Formenti, A., additional, Cortinovis, S., additional, Ballerini, G., additional, Fiorentini, C., additional, Pepi, M., additional, Koh, A. S., additional, Flores, J. S., additional, Keng, F. Y. J., additional, Tan, R. S., additional, Chua, T. S. J., additional, Annoni, A. D., additional, Tamborini, G., additional, Fusari, M., additional, Bartorelli, A. L., additional, Ewe, S. H., additional, Ng, A. C. T., additional, Delgado, V., additional, Schuijf, J., additional, Van Der Kley, F., additional, Colli, A., additional, De Weger, A., additional, Marsan, N. A., additional, Yiu, K. H., additional, Ng, A. C., additional, Timmer, S. A. J., additional, Knaapen, P., additional, Germans, T., additional, Dijkmans, P. A., additional, Lubberink, M., additional, Ten Berg, J. M., additional, Ten Cate, F. J., additional, Russel, I. K., additional, Lammertsma, A. A., additional, Van Rossum, A. C., additional, Wong, Y. Y., additional, Ruiter, G., additional, Raijmakers, P., additional, Van Der Laarse, W. J., additional, Westerhof, N., additional, Vonk-Noordegraaf, A., additional, Youssef, G., additional, Leung, E., additional, Wisenberg, G., additional, Marriot, C., additional, Williams, K., additional, Etele, J., additional, Dekemp, R. A., additional, Dasilva, J., additional, Birnie, D., additional, Beanlands, R. S. B., additional, Thompson, R. C., additional, Allam, A. H., additional, Wann, L. S., additional, Nureldin, A. H., additional, Adelmaksoub, G., additional, Badr, I., additional, Sutherland, M. L., additional, Sutherland, J. D., additional, Miyamoto, M. I., additional, Thomas, G. S., additional, Harms, H. J., additional, De Haan, S., additional, Huisman, M. C., additional, Schuit, R. C., additional, Windhorst, A. D., additional, Allaart, C., additional, Einstein, A. J., additional, Khawaja, T., additional, Greer, C., additional, Chokshi, A., additional, Jones, M., additional, Schaefle, K., additional, Bhatia, K., additional, Shimbo, D., additional, Schulze, P. C., additional, Srivastava, A., additional, Chettiar, R., additional, Moody, J., additional, Weyman, C., additional, Natale, D., additional, Bruni, W., additional, Liu, Y., additional, Ficaro, E., additional, Sinusas, A. J., additional, Peix, A., additional, Batista, E., additional, Cabrera, L. O., additional, Padron, K., additional, Rodriguez, L., additional, Sainz, B., additional, Mendoza, V., additional, Carrillo, R., additional, Fernandez, Y., additional, Mena, E., additional, Naum, A., additional, Bach-Gansmo, T., additional, Kleven-Madsen, N., additional, Biermann, M., additional, Johnsen, B., additional, Aase Husby, J., additional, Rotevatn, S., additional, Nordrehaug, J. E., additional, Schaap, J., additional, Kauling, R. M., additional, Post, M. C., additional, Rensing, B. J. W. M., additional, Verzijlbergen, J. F., additional, Sanchez, J., additional, Giamouzis, G., additional, Tziolas, N., additional, Georgoulias, P., additional, Karayannis, G., additional, Chamaidi, A., additional, Zavos, N., additional, Koutrakis, K., additional, Sitafidis, G., additional, Skoularigis, J., additional, Triposkiadis, F., additional, Radovanovic, S., additional, Djokovic, A., additional, Simic, D. V., additional, Krotin, M., additional, Savic-Radojevic, A., additional, Pljesa-Ercegovac, M., additional, Zdravkovic, M., additional, Saponjski, J., additional, Jelic, S., additional, Simic, T., additional, Eckardt, R., additional, Kjeldsen, B. J., additional, Andersen, L. I., additional, Haghfelt, T., additional, Grupe, P., additional, Johansen, A., additional, Hesse, B., additional, Pena, H., additional, Cantinho, G., additional, Wilk, M., additional, Srour, Y., additional, Godinho, F., additional, Zafrir, N., additional, Gutstein, A., additional, Mats, I., additional, Battler, A., additional, Solodky, A., additional, Sari, E., additional, Singh, N., additional, Vara, A., additional, Peters, A. M., additional, De Belder, A., additional, Nair, S., additional, Ryan, N., additional, James, R., additional, Dizdarevic, S., additional, Depuey, G., additional, Friedman, M., additional, Wray, R., additional, Old, R., additional, Babla, H., additional, Chuanyong, B., additional, Maddahi, J., additional, Tragardh Johansson, E., additional, Sjostrand, K., additional, Edenbrandt, L., additional, Aguade-Bruix, S., additional, Cuberas-Borros, G., additional, Pizzi, M. N., additional, Sabate-Fernandez, M., additional, De Leon, G., additional, Garcia-Dorado, D., additional, Castell-Conesa, J., additional, Candell-Riera, J., additional, Casset-Senon, D., additional, Edjlali-Goujon, M., additional, Alison, D., additional, Delhommais, A., additional, Cosnay, P., additional, Low, C. S., additional, Notghi, A., additional, O'brien, J., additional, Tweddel, A. C., additional, Bingham, N., additional, O Neil, P., additional, Harbinson, M., additional, Lindner, O., additional, Burchert, W., additional, Schaefers, M., additional, Marcassa, C., additional, Campini, R., additional, Calza, P., additional, Zoccarato, O., additional, Kisko, A., additional, Kmec, J., additional, Babcak, M., additional, Vereb, M., additional, Vytykacova, M., additional, Cencarik, J., additional, Gazdic, P., additional, Stasko, J., additional, Abreu, A., additional, Pereira, E., additional, Oliveira, L., additional, Colarinha, P., additional, Veloso, V., additional, Enriksson, I., additional, Proenca, G., additional, Delgado, P., additional, Rosario, L., additional, Sequeira, J., additional, Kosa, I., additional, Vassanyi, I., additional, Egyed, C. S., additional, Kozmann, G. Y., additional, Morita, S., additional, Nanasato, M., additional, Nanbu, I., additional, Yoshida, Y., additional, Hirayama, H., additional, Allam, A., additional, Sharef, A., additional, Shawky, I., additional, Farid, M., additional, Mouden, M., additional, Ottervanger, J. P., additional, Timmer, J. R., additional, De Boer, M. J., additional, Reiffers, S., additional, Jager, P. L., additional, Knollema, S., additional, Nasr, G. M., additional, Mohy Eldin, M., additional, Ragheb, M., additional, Casans-Tormo, I., additional, Diaz-Exposito, R., additional, Hurtado-Mauricio, F. J., additional, Ruano, R., additional, Diego, M., additional, Gomez-Caminero, F., additional, Albarran, C., additional, Martin De Arriba, A., additional, Rosero, A., additional, Lopez, R., additional, Martin Luengo, C., additional, Garcia-Talavera, J. R., additional, Laitinen, I. E. K., additional, Rudelius, M., additional, Weidl, E., additional, Henriksen, G., additional, Wester, H. J., additional, Schwaiger, M., additional, Pan, X. B., additional, Schindler, T., additional, Quercioli, A., additional, Zaidi, H., additional, Ratib, O., additional, Declerck, J. M., additional, Alexanderson Rosas, E., additional, Jacome, R., additional, Jimenez-Santos, M., additional, Romero, E., additional, Pena-Cabral, M. A., additional, Meave, A., additional, Gonzalez, J., additional, Rouzet, F., additional, Bachelet, L., additional, Alsac, J. M., additional, Suzuki, M., additional, Louedec, L., additional, Petiet, A., additional, Chaubet, F., additional, Letourneur, D., additional, Michel, J. B., additional, Le Guludec, D., additional, Aktas, A., additional, Cinar, A., additional, Yaman, G., additional, Bahceci, T., additional, Kavak, K., additional, Gencoglu, A., additional, Jimenez-Heffernan, A., additional, Sanchez De Mora, E., additional, Lopez-Martin, J., additional, Lopez-Aguilar, R., additional, Ramos, C., additional, Salgado, C., additional, Ortega, A., additional, Sanchez-Gonzalez, C., additional, Roa, J., additional, Tobaruela, A., additional, Nesterov, S. V., additional, Turta, O., additional, Maki, M., additional, Han, C., additional, Daou, D., additional, Tawileh, M., additional, Chamouine, S. O., additional, Coaguila, C., additional, Mariscal-Labrador, E., additional, Kisiel-Gonzalez, N., additional, De Araujo Goncalves, P., additional, Sousa, P. J., additional, Marques, H., additional, O'neill, J., additional, Pisco, J., additional, Cale, R., additional, Brito, J., additional, Gaspar, A., additional, Machado, F. P., additional, Roquette, J., additional, Martinez, M., additional, Melendez, G., additional, Kimura, E., additional, Ochoa, J. M., additional, Alessio, A. M., additional, Patel, A., additional, Lautamaki, R., additional, Bengel, F. M., additional, Bassingthwaighte, J. B., additional, Caldwell, J. H., additional, Rahbar, K., additional, Seifarth, H., additional, Schafers, M., additional, Stegger, L., additional, Spieker, T., additional, Hoffmeier, A., additional, Maintz, D., additional, Scheld, H., additional, Schober, O., additional, Weckesser, M., additional, Aoki, H., additional, Matsunari, I., additional, Kajinami, K., additional, Martin Fernandez, M., additional, Barreiro Perez, M., additional, Fernandez Cimadevilla, O. V., additional, Leon Duran, D., additional, Velasco Alonso, E., additional, Florez Munoz, J. P., additional, Luyando, L. H., additional, Templin, C., additional, Veltman, C. E., additional, Reiber, J. H. C., additional, Venuraju, S., additional, Yerramasu, A., additional, Atwal, S., additional, Lahiri, A., additional, Kunimasa, T., additional, Shiba, M., additional, Ishii, K., additional, Aikawa, J., additional, Kroner, E. S. J., additional, Ho, K. T., additional, Yong, Q. W., additional, Chua, K. C., additional, Panknin, C., additional, Roos, C. J., additional, Van Werkhoven, J. M., additional, Witkowska-Grzeslo, A. J., additional, Boogers, M. J., additional, Anand, D. V., additional, Dey, D., additional, Berman, D., additional, Mut, F., additional, Giubbini, R., additional, Lusa, L., additional, Massardo, T., additional, Iskandrian, A., additional, Dondi, M., additional, Sato, A., additional, Kakefuda, Y., additional, Ojima, E., additional, Adachi, T., additional, Atsumi, A., additional, Ishizu, T., additional, Seo, Y., additional, Hiroe, M., additional, Aonuma, K., additional, Kruk, M., additional, Pracon, R., additional, Kepka, C., additional, Pregowski, J., additional, Kowalewska, A., additional, Pilka, M., additional, Opolski, M., additional, Michalowska, I., additional, Dzielinska, Z., additional, Demkow, M., additional, Stoll, V., additional, Sabharwal, N., additional, Chakera, A., additional, Ormerod, O., additional, Fernandes, H., additional, Bernardes, M., additional, Martins, E., additional, Oliveira, P., additional, Vieira, T., additional, Terroso, G., additional, Oliveira, A., additional, Faria, T., additional, Ventura, F., additional, Pereira, J., additional, Fukuzawa, S., additional, Inagaki, M., additional, Sugioka, J., additional, Ikeda, A., additional, Okino, S., additional, Maekawa, J., additional, Uchiyama, T., additional, Kamioka, N., additional, Ichikawa, S., additional, Afshar, M., additional, Alvi, R., additional, Aguilar, N., additional, Ippili, R., additional, Shaqra, H., additional, Bella, J., additional, Bhalodkar, N., additional, Dos Santos, A., additional, Daicz, M., additional, Cendoya, L. O., additional, Marrero, H. G., additional, Casuscelli, J., additional, Embon, M., additional, Vera Janavel, G., additional, Duronto, E., additional, Gurfinkel, E. P., additional, Cortes, C. M., additional, Takeishi, Y., additional, Nakajima, K., additional, Yamasaki, Y., additional, Nishimura, T., additional, Hayes Brown, K., additional, Collado, F., additional, Alhaji, M., additional, Green, J., additional, Alexander, S., additional, Vashistha, R., additional, Jain, S., additional, Aldaas, F., additional, Shanes, J., additional, Doukky, R., additional, Ashikaga, K., additional, Akashi, Y. J., additional, Uemarsu, M., additional, Kamijima, R., additional, Yoneyama, K., additional, Omiya, K., additional, Miyake, Y., additional, Brodov, Y., additional, Raval, U., additional, Berezin, A., additional, Seden, V., additional, Koretskaya, E., additional, Panasenko, T. A., additional, Matsuo, S., additional, Kinuya, S., additional, Chen, J., additional, Van Bommel, R. J., additional, Van Der Hiel, B., additional, Dibbets-Schneider, P., additional, Garcia, E. V., additional, Rutten-Vermeltfoort, I., additional, Gevers, M. M. J., additional, Verhoeven, B., additional, Dijk Van, A. B., additional, Raaijmakers, E., additional, Raijmakers, P. G. H. M., additional, Engvall, J. E., additional, Gjerde, M., additional, De Geer, J., additional, Olsson, E., additional, Quick, P., additional, Persson, A., additional, Mazzanti, M., additional, Marini, M., additional, Pimpini, L., additional, Perna, G. P., additional, Marciano, C., additional, Gargiulo, P., additional, Galderisi, M., additional, D'amore, C., additional, Savarese, G., additional, Casaretti, L., additional, Paolillo, S., additional, Cuocolo, A., additional, Perrone Filardi, P., additional, Al-Amoodi, M., additional, Thompson, E. C., additional, Kennedy, K., additional, Bybee, K. A., additional, Mcghie, A. I., additional, O'keefe, J. H., additional, Bateman, T. M., additional, Van Der Palen, R. L. F., additional, Mavinkurve-Groothuis, A. M., additional, Bulten, B., additional, Bellersen, L., additional, Van Laarhoven, H. W. M., additional, Kapusta, L., additional, De Geus-Oei, L. F., additional, Pollice, P. P., additional, Bonifazi, M. B., additional, Pollice, F. P., additional, Clements, I. P., additional, Hodge, D. O., additional, Scott, C. G., additional, De Ville De Goyet, M., additional, Brichard, B., additional, Pirotte, T., additional, Moniotte, S., additional, Tio, R. A., additional, Elvan, A., additional, Dierckx, R. A. I. O., additional, Slart, R. H. J. A., additional, Furuhashi, T., additional, Moroi, M., additional, Hase, H., additional, Joki, N., additional, Masai, H., additional, Nakazato, R., additional, Fukuda, H., additional, Sugi, K., additional, Kryczka, K., additional, Kaczmarska, E., additional, Petryka, J., additional, Mazurkiewicz, L., additional, Ruzyllo, W., additional, Smanio, P., additional, Vieira Segundo, E., additional, Siqueira, M., additional, Kelendjian, J., additional, Ribeiro, J., additional, Alaca, J., additional, Oliveira, M., additional, Alves, F., additional, Peovska, I., additional, Maksimovic, J., additional, Vavlukis, M., additional, Kostova, N., additional, Pop Gorceva, D., additional, Majstorov, V., additional, Zdraveska, M., additional, Hussain, S., additional, Djearaman, M., additional, Hoey, E., additional, Morus, L., additional, Erinfolami, O., additional, Macnamara, A., additional, Opolski, M. P., additional, Witkowski, A., additional, Berti, V., additional, Ricci, F., additional, Gallicchio, R., additional, Acampa, W., additional, Cerisano, G., additional, Vigorito, C., additional, Sciagra', R., additional, Pupi, A., additional, Sliem, H., additional, Collado, F. M., additional, Schmidt, S., additional, Maheshwari, A., additional, Kiriakos, R., additional, Mwansa, V., additional, Ljubojevic, S., additional, Sedej, S., additional, Holzer, M., additional, Marsche, G., additional, Marijanski, V., additional, Kockskaemper, J., additional, Pieske, B., additional, Ricalde, A., additional, Alexanderson, G., additional, Mohani, A., additional, Khanna, P., additional, Sinusas, A., additional, Lee, F., additional, Pinas, V. A., additional, Van Eck-Smit, B. L. F., additional, Verberne, H. J., additional, De Bruin, C. M., additional, Guilhermina, G., additional, Jimenez-Angeles, L., additional, Ruiz De Jesus, O., additional, Yanez-Suarez, O., additional, Vallejo, E., additional, Reyes, E., additional, Chan, M., additional, Hossen, M. L., additional, Underwood, S. R., additional, Karu, A., additional, Bokhari, S., additional, Pineda, V., additional, Gracia-Sanchez, L. M., additional, Garcia-Burillo, A., additional, Zavadovskiy, K., additional, Lishmanov, Y. U., additional, Saushkin, W., additional, Kovalev, I., additional, Chernishov, A., additional, Annoni, A., additional, Tarkia, M., additional, Saanijoki, T., additional, Oikonen, V., additional, Savunen, T., additional, Green, M. A., additional, Strandberg, M., additional, Roivainen, A., additional, Gaeta, M. C., additional, Artigas, C., additional, Deportos, J., additional, Geraldo, L., additional, Flotats, A., additional, La Delfa, V., additional, Carrio, I., additional, Laarse, W. J., additional, Izquierdo Gomez, M. M., additional, Lacalzada Almeida, J., additional, Barragan Acea, A., additional, De La Rosa Hernandez, A., additional, Juarez Prera, R., additional, Blanco Palacios, G., additional, Bonilla Arjona, J. A., additional, Jimenez Rivera, J. J., additional, Iribarren Sarrias, J. L., additional, Laynez Cerdena, I., additional, Dedic, A., additional, Rossi, A., additional, Ten Kate, G. J. R., additional, Dharampal, A., additional, Moelker, A., additional, Galema, T. W., additional, Mollet, N., additional, De Feyter, P. J., additional, Nieman, K., additional, Trabattoni, D., additional, Broersen, A., additional, Frenay, M., additional, Boogers, M. M., additional, Kitslaar, P. H., additional, Dijkstra, J., additional, Annoni, D. A., additional, Muratori, M., additional, Johki, N., additional, Tokue, M., additional, Dharampal, A. S., additional, Weustink, A. C., additional, Neefjes, L. A. E., additional, Papadopoulou, S. L., additional, Chen, C., additional, Mollet, N. R. A., additional, Boersma, E. H., additional, Krestin, G. P., additional, Purvis, J. A., additional, Sharma, D., additional, Hughes, S. M., additional, Berman, D. S., additional, Taillefer, R., additional, Udelson, J., additional, Devine, M., additional, Lazewatsky, J., additional, Bhat, G., additional, Washburn, D., additional, Patel, D., additional, Mazurek, T., additional, Tandon, S., additional, Bansal, S., additional, Inzucchi, S., additional, Staib, L., additional, Davey, J., additional, Chyun, D., additional, Young, L., additional, Wackers, F., additional, Harbinson, M. T., additional, Wells, G., additional, Dougan, J., additional, Borges-Neto, S., additional, Phillips, H., additional, Farzaneh-Far, A., additional, Starr, Z., additional, Shaw, L. K., additional, Fiuzat, M., additional, O'connor, C., additional, Henzlova, M., additional, Duvall, W. 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2011
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33. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice.

Author

Ledent, Catherine, Valverde, Olga, Cossu, G, Petitet, F, Aubert, J F, Beslot, F, Böhme, Georg Andrees, Imperato, Assunta, Pedrazzini, T, Roques, Bernard P, Vassart, Gilbert, Fratta, W, Parmentier, Marc, Ledent, Catherine, Valverde, Olga, Cossu, G, Petitet, F, Aubert, J F, Beslot, F, Böhme, Georg Andrees, Imperato, Assunta, Pedrazzini, T, Roques, Bernard P, Vassart, Gilbert, Fratta, W, and Parmentier, Marc

Abstract

The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
1999

40. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor.

Author

Ledent, Catherine, Vaugeois, Jean-Marie, Schiffmann, Serge N., Pedrazzini, T, El Yacoubi, Malika, Vanderhaeghen, Jean-Jacques, Costentin, Jean, Heath, J K, Vassart, Gilbert, Parmentier, Marc, Ledent, Catherine, Vaugeois, Jean-Marie, Schiffmann, Serge N., Pedrazzini, T, El Yacoubi, Malika, Vanderhaeghen, Jean-Jacques, Costentin, Jean, Heath, J K, Vassart, Gilbert, and Parmentier, Marc

Abstract

Adenosine is released from metabolically active cells by facilitated diffusion, and is generated extracellularly by degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types, including various neuronal populations, platelets, neutrophils and mast cells, and smooth muscle cells in bronchi and vasculature. Most of these effects help to protect cells and tissues during stress conditions such as ischaemia. Adenosine mediates its effects through four receptor subtypes: the A1, A2a, A2b and A3 receptors. The A2a receptor (A2aR) is abundant in basal ganglia, vasculature and platelets, and stimulates adenylyl cyclase. It is a major target of caffeine, the most widely used psychoactive drug. Here we investigate the role of the A2a receptor by disrupting the gene in mice. We found that A2aR-knockout (A2aR-/-) mice were viable and bred normally. Their exploratory activity was reduced, whereas caffeine, which normally stimulates exploratory behaviour, became a depressant of exploratory activity. Knockout animals scored higher in anxiety tests, and male mice were much more aggressive towards intruders. The response of A2aR-/- mice to acute pain stimuli was slower. Blood pressure and heart rate were increased, as well as platelet aggregation. The specific A2a agonist CGS 21680 lost its biological activity in all systems tested., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
1997

50. Functional responsivenessin vitro andin vivo of α/β T cell receptors expressed by the B2A2 (J11d)– subset of CD4–8– thymocytes

Author

Pedrazzini T, H R MacDonald, and Rawleigh C. Howe

Subjects
Antigens, Differentiation, T-Lymphocyte, Cytotoxicity, Immunologic, Interleukin 2, CD3, Immunology, Receptors, Antigen, T-Cell, Biology, Lymphocyte Activation, Mice, medicine, Animals, Immunology and Allergy, Beta (finance), Receptor, Mice, Inbred BALB C, T-cell receptor, Lymphokine, Antibodies, Monoclonal, Molecular biology, Mice, Inbred C57BL, Cytolysis, Thymocyte, Phenotype, biology.protein, Interleukin-2, Female, Binding Sites, Antibody, T-Lymphocytes, Cytotoxic, medicine.drug
Abstract

B2A2-CD4-8- cells represent a rare subpopulation of thymocytes normally comprising 0.5% of the total adult thymus. These cells are known to express CD3-associated T cell receptor (TcR) alpha/beta molecules. In the present study we have examined the functional capacity of alpha/beta heterodimers on B2A2-CD4-8- cells. In the presence of monoclonal antibody (mAb) specific for either murine CD3 or TcR expressing the V beta 8-encoded beta chain (F23.1), B2A2-CD4-8- cells proliferated. Such proliferation was blocked by mAb to interleukin 2 receptor (IL 2R), suggesting an autocrine mechanism involving IL 2 production and subsequent utilization. IL 2 and also IL 3 production by mAb-stimulated B2A2-CD4-8- cells was directly confirmed. Furthermore, a panel of B2A2-CD4-8- clones were derived to assess the role of the TcR in cytolysis. Many clones were isolated which killed Fc receptor-bearing P815 target cells only in the presence of F23.1 mAb. Finally, in vivo treatment of neonatal mice with F23.1 mAb resulted in a marked reduction of V beta 8+ B2A2-CD4-8- thymocytes. Collectively, these results indicate that the TcR alpha/beta complex on CD4-CD8-B2A2- cells is fully capable of transducing signals that lead to proliferation, lymphokine production and cytolysis in vitro, as well as to disappearance of this subset from the thymus in vivo.

Published
1989

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