News - Institute of Pharmacology
News
Essen, 18.01.2015
Inaugural Lecture Priv.-Doz. Dr. med. Niels Voigt
On January 16, 2015 at 15:00h, PD Dr. med. Niels Voigt gave his inaugural lecture: 'Mord aus zarter Hand – Berühmte Giftmorde aus Sicht eines Pharmakologen' as part of the completion of his habilitation. Dr. Voigt spoke about three famous cases of poisoning known from popular literature and analyzed them from the point of view of a pharmacologist. The lecture-hall (Deichmann-Auditorium) was almost fully occupied.
Essen, 15.01.2015
Drs. Voigt and Heijman win the 2015 Oskar Lapp Research Award of the German Cardiac Society
Priv.-Doz. Dr. med. Niels Voigt and Dr. Jordi Heijman of the Institute of Pharmacology have been awarded the Oskar Lapp Research Award (Oskar-Lapp-Forschungspreis) 2015 of the German Cardiac Society (Deutsche Gesellschaft für Kardiologie, DGK) for their joint publication ‘Cellular and Molecular Mechanims of Atrial Arrhythmogenesis in Patients with Paroxysmal Atrial Fibrillation’ (Circulation 2014. 129: 145-156). The Oskar Lapp Research Award is an important award for scientists <35 years. It is the first award of the DGK without thematic restrictions. Its intention is to expand the horizons of human medicine. The award will be presented as part of the opening ceremony of the 81st Annual Meeting of the DGK on April 9, 2015 in Mannheim, Germany.
Essen, 19.12.2014
Invitation Inaugural Lecture PD Dr. med. Niels Voigt
On January 16, 2015 at 15:00h, PD Dr. med. Niels Voigt will give his inaugural lecture: 'Mord aus zarter Hand – Berühmte Giftmorde aus Sicht eines Pharmakologen' as part of the completion of his habilitation. The official invitation can be found here.
Essen, 17.12.2014
Merry Christmas from the Institute of Pharmacology
The Institute of Pharmacology wishes everyone a happy holiday season, merry Christmas, and all the best for 2015!
Essen, 07.11.2014
Institute of Pharmacology hosts the EUTRAF review meeting
On Tuesday, November 4, and Wednesday November 5, the Institute of Pharmacology hosted the 4th year review meeting of the “The European Network for Translational Research in Atrial Fibrillation” (EUTRAF), a European network funded as part of the FP7 program. Approximately 50 scientists traveled to Essen and, after a welcome by Prof. Dr. Forsting, vice-dean of research of the Faculty of Medicine, University Duisburg-Essen, and Prof. Dr. Heusch, director of the Institute of Pathophysiology, and chair of the West German Heart and Vascular Center, exchanged the latest results in translational atrial fibrillation research.
Essen, 31.08.2014
Ca2+/Calmodulin-dependent Protein Kinase Type-II induces maladaptive cardiac remodeling but inhibits calcineurin-induced myocardial hypertrophy
Prof. Dobrev, director of the Institute of Pharmacology contributed to a study published in Circulation by the group of Prof. Johannes Backs from the University of Heidelberg. The study by Kreusser et al. (Circulation 2014; published online on August 15) shows for the first time that both the Ca2+/calmodulin-dependent protein kinase type-II (CaMKII) δ and γ isoforms contribute to the phosphorylation of various targets, including phospholamban, the cardiac ryanodine receptor, and protein phosphatase calcineurin. Double knock-out mice lacking CaMKIIδ and CaMKIIγ were protected from cardiac dysfunction and interstitial fibrosis following pathological pressure overload. Interestingly, however, double knock-out mice did develop cardiac hypertrophy, which was found to be due to excessive calcineurin activation resulting from a lack of CaMKII-dependent phosphorylation of the auto-inhibitory site Ser411 of calcineurin. Taken together, this novel mouse model, in which CaMKII activity is specifically and completely abolished, shows that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII, but not calcineurin, as a promising approach to attenuate the progression of heart failure.
Reference:
Kreusser MM, Lehmann LH, Keranov S, Hoting M-O, Kohlhaas M, Reil J-C, Neumann K, Schneider MD, Hill JA, Dobrev D, Maack C, Maier LS, Gröne H-J, Katus HA, Olson EN, Backs J (2014) The cardiac CaMKII genes δ and γ contribute redundantly to adverse remodeling but inhibit calcineurin-induced myocardial hypertrophy. Circulation, published online on Aug 15 (DOI:10.1161/CIRCULATIONAHA.114.006185).
Essen, 19.06.2014
Prof. Dobrev joins the Editorial Board of Circulation
Prof. Dobrev was asked and joined the Editorial Board of the journal Circulation. Circulation is a weekly peer-reviewed medical journal published by Lippincott Williams & Wilkins and is the official journal of the American Heart Association. The Journal ranks #1 among journals in the Cardiac & Cardiovascular Systems category and #1 among journals in the Peripheral Vascular Disease category (according to the 2012 Journal Citation Reports®, Thomson Reuters, 2013). A link to the journal can be found here: http://circ.ahajournals.org/
Essen, 06.06.2014
Dr. Niels Voigt completes habilitation
Yesterday, Dr. Niels Voigt successfully completed his habilitation with a presentation for the faculty council on generic drugs, addressing the question whether they are a true equivalent to the original preparation. In Germany, the habilitation (from Latin “habilis”, meaning "fit, proper, skillful") is the highest academic qualification a scholar can achieve by his own pursuit. It requires publication of numerous papers, as well as teaching duties. The Institute of Pharmacology congratulates Dr. Voigt with this important milestone!
Essen, 21.05.2014
Circulation Research Atrial Fibrillation Compendium
Members of the Institute of Pharmacology contributed to the most recent Compendium in Circulation Research about Atrial Fibrillation (AF). The AF compendium, which was edited by Prof. Stanley Nattel (Montreal Heart Institute, Montreal, Canada), provides a collection of review articles describing the clinical profile, genetic underpinnings, and cellular and molecular mechanisms of AF, as well as reviews of the role of the autonomic nervous system, mathematical approaches to understanding AF, and AF therapy. In particular, members of the Institute of Pharmacology wrote the article ´Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression´ and contributed to ´The Clinical Profile and Pathophysiology of Atrial Fibrillation: Relationships Among Clinical Features, Epidemiology, and Mechanisms´. According to Circulation Research, these compendia are considered “a one-stop shop for basic, translational, and clinical investigators who wish to gather a comprehensive assessment of a problem” (link)
References:
Heijman J*, Voigt N*, Nattel S, Dobrev D (2014) Compendium: Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance and Progression. Circ Res, 114(9): 1483-1499. *equally contributed first authors
Andrade J, Khairy P, Dobrev D, Nattel S (2014) The Clinical Profile and Pathophysiology of Atrial Fibrillation: Relationships among Clinical Features, Epidemiology, and Mechanisms. Circ Res, 114(9): 1453-1468.
Essen, 27.03.2014
Visit Prof. Stanley Nattel
On Tuesday, March 25th and Wednesday March 26th, the Institute of Pharmacology was proud to have Prof. Stanley Nattel (Department of Medicine, Montreal Heart Institute and Université de Montréal and Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada) as a guest. Prof. Nattel gave a well-attended presentation as part of the Faculty of Medicine Seminar Series and was involved in numerous discussions with members of the institute about joint projects.
Essen, 18.03.2014
Visit Prof. Xander Wehrens
On Monday, March 17, long-term collaborator Prof. Xander Wehrens (Cardiovascular Research Institute, Departments of Molecular Physiology and Biophysics, and Medicine-Cardiology, Baylor College of Medicine, Houston, TX) visited the Institute of Pharmacology. Prof. Wehrens presented recent data from his lab about the role of cardiac ryanodine receptor channel regulation in atrial fibrillation and participated in discussions about ongoing collaborative projects.
Essen, 01.03.2014
Prof. Dr. Fritz Sörgel interviewed about athletes and doping
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Prof. Dr. Fritz Sörgel, associate member of the Insitute of Pharmacology and director of the Institute for Biomedical and Pharmaceutical Research (IBPM) was recently interviewed by several media including the German “Ärztezeitung” about his expertise in the field of doping. The article “Für Gold würden viele sterben” (in German) can be found Essen, 14.01.2014
Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation
Atrial fibrillation (AF) is the most common arrhythmia with increasing incidence in aging population. Although the cellular electrophysiological abnormalities in patients with long-standing persistent AF had been studied in some detail before, the atrial-cellular pathophysiology in patients with paroxysmal AF (pAF) was largely unknown until now.
Members of the Institute of Pharmacology published a study in the most recent edition of Circulation (Voigt et al. Circulation 2014; 129(2): 145-156), showing for the first time the cellular and molecular mechanisms contributing to atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation (AF). This paper was selected for presentation in the “Best of Basic Science” Session at the Annual Meeting of the American Heart Association (Dallas, USA) and following expedited editorial consideration appeared simultaneously online on November 18, 2013, in Circulation.
In this study, simultaneous measurements of intracellular [Ca2+] and membrane current/potential in atrial cardiomyocytes from sinus rhythm and pAF patients showed that L-type Ca2+ currents and action potential durations were unaltered in pAF, pointing to the absence of typical AF-promoting atrial remodeling. However, cardiomyocytes from pAF patients showed Ca2+-handling abnormalities including enhanced diastolic sarcoplasmic reticulum (SR) Ca2+ leak and increased susceptibility to spontaneous diastolic SR Ca2+-release events, causing proarrhythmic delayed afterdepolarizations and ectopic (triggered) activities.
Pharmacological and biochemical studies indicated that the susceptibility to spontaneous cellular activity in pAF was attributable to enhanced SR Ca2+ uptake, resulting from phospholamban hyperphosphorylation, and ryanodine receptor (SR Ca2+-release) channel dysregulation. Simulation studies indicated that both these factors likely contribute synergistically to aberrant diastolic SR Ca2+-release events.
Our findings constitute the first direct evidence for an important role of Ca2+-dependent ectopic activity in atrial arrhythmogenesis of pAF patients and provide insights into underlying mechanisms. The cellular and molecular mechanisms underlying abnormal Ca2+ handling in pAF are distinct from those of long-standing persistent AF patients, suggesting possible opportunities to develop tailored therapeutic approaches for pAF.
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Essen, 17.12.2013
Manuscript highlighted in the Journal of the American College of Cardiology’s “The Year in Review of Clinical Cardiac Electrophysiology”
A paper written by members from the Institute of Pharmacology was highlighted in the most recent edition of the Journal of the American College of Cardiology as part of “The Year in Review of Clinical Cardiac Electrophysiology” (J. Am. Coll. Cardiol. 2013; 65:2433-2447).
In this publication (Voigt et al. Circulation. 2012;125:2059-2070), we showed that atrial myocytes isolated from right atrial appendages from patients with chronic atrial fibrillation (cAF) exhibit potentially proarrhythmic Ca2+-handling abnormalities. We assessed the underlying molecular mechanisms, and identified a causal role for Ca2+/calmodulin-dependent protein kinase-II (CaMKII)-dependent dysfunction of ryanodine receptor type-2 channels, contributing to abnormal (increased) diastolic Ca2+ leak from the sarcoplasmic reticulum and a greater incidence of spontaneous sarcoplasmic reticulum Ca2+-release events. In addition, an increased Na+/Ca2+exchanger expression in cAF resulted in an enhanced depolarizing transient-inward current for any given diastolic Ca2+-release. Together, these factors contributed to AF-promoting atrial delayed afterdepolarizations in AF patients. Our results show for the first time that delayed afterdepolarizations and related ectopic (triggered) activity may contribute to induction and maintenance of AF in patients constituting a potential target for future anti-AF therapy.
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Essen, 30.10.2013
Dr. Jordi Heijman receives CARIM Dissertation Award 2011/2012
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Dr. Jordi Heijman received the 2011/2012 dissertation award of the Cardiovascular Research Institute Maastricht (CARIM) for his PhD thesis entitled "Computational analysis of β-adrenergic stimulation and its effects on cardiac ventricular electrophysiology". The award was presented by Prof. Dr. Thomas Unger, scientific director of CARIM, during CARIM's 25 year anniversary.
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Essen, 17.10.2013
Oxidized Ca2+/Calmodulin-dependent Protein Kinase Type-II Triggers Atrial Fibrillation in Mice
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Members of the Institute of Pharmacology contributed to a study published in the most recent edition of Circulation by the group of Prof. Anderson of the University of Iowa. The study by Purohit et al. (Circulation 2013; 128(16): 1748-1757) shows for the first time that the Ca2+/calmodulin-dependent protein kinase type-II (CaMKII) provides a molecular signal linking increased reactive oxygen species and Ca2+ signaling to atrial fibrillation (AF). In particular, levels of oxidized CaMKII were increased in patients with AF. Elevation of reactive-oxygen species through infusion of angiotensin-II and subsequent oxidation of CaMKII increased the susceptibility to pacing-induced AF in wild-type mice by promoting Ca2+-handling abnormalities. However, mice with myocardium-restricted overexpression of methionine sulfoxide reductase A (an enzyme reducing CaMKII oxidation) or knock-in mice which had critical CaMKIIδ oxidation sites disabled were resistant to AF induction following angiotensin-II infusion. Taken together, these studies highlight a critical role for CaMKII oxidation in linking increased reactive oxygen species and AF.
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Essen, 25.09.2013
Visit Prof Stanley Nattel and 2013 ENAFRA Leducq Meeting
On Tuesday, August 27, Prof. Stanley Nattel (Department of Medicine, Montreal Heart Institute and Université de Montréal and Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada) visited the Institute of Pharmacology. That evening, all scientific members of the institute travelled together with Prof. Nattel to Maastricht, The Netherlands, for the final meeting of the European/North-American Atrial Fibrillation Research Alliance (ENAFRA), an international network funded by Fondation Leducq.
Essen, 30.05.2013
Dr. Niels Voigt obtaines medical specialization in pharmacology and toxicology
Dr. Niels Voigt has obtained his medical specialization in pharmacology and toxicology ("Facharzt für Pharmakologie und Toxikologie").
Essen, 18.04.2013
Dr. Niels Voigt receives travel grant EWGCCE
Dr. Niels Voigt has received a travel award to attend the 37th Annual Meeting of the European Working Group on Cardiac Cellular Electrophysiology (EWGCCE) in Athens, Greece in June 2013.
Essen, 10.04.2013
MicroRNA29: A Mechanistic Contributor and Potential Biomarker in Atrial Fibrillation
In the most recent edition of Circulation, members of the Institute of Pharmacology contributed to a study by the group of Prof. Nattel of the Montreal Heart Institute identifying a critical role for microRNA (miR) 29b in atrial fibrotic remodeling. In the study by Dawson et al. (Circulation 2013;127:1466-1475), it was shown that miR29b is rapidly decreased in a dog model of ventricular pacing and that plasma levels of miR29b are decreased in patients with atrial fibrillation, heart failure, or both. Of note, the latter group showed significantly lower levels than those with atrial fibrillation or heart failure alone. MiR29b inhibits expression of several profibrotic genes including collagen 1A1, collagen 3A1 and fibrillin and the reduction in miR29b in fibroblasts was associated with elevated levels of these profibrotic targets. Importantly, an in vivo reduction of miR29b using adenovirus-mediated overexpression of a mir29B ‘sponge’ in mice was associated with increased fibrosis. Taken together, our work suggests for the first time that miR29b is a strong candidate to modulate atrial structural remodeling and has potential as a candidate biomarker for atrial fibrillation.
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Essen, 26.03.2013
Two papers highlighted in Circulation’s ‘Most Read Articles in Arrhythmia and Electrophysiology’
Two papers co-authored by members of the Institute of Pharmacology where highlighted in the most recent edition of Circulation Editors’ Picks: Most Read Articles in Arrhythmia and Electrophysiology (Circulation. 2013; 127:e509-519).
In the first paper that was highlighted (Voigt et al. Circulation. 2012;125:2059-2070), we showed that atrial myocytes isolated from right atrial appendages from patients with chronic atrial fibrillation (AF) showed pronounced Ca2+-handling abnormalities compared to myocytes from patients in sinus rhythm. Ryanodine receptor channels showed a Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent increase in open probability in AF, contributing to increased Ca2+ leak from the sarcoplasmic reticulum and an increased incidence of spontaneous sarcoplasmic reticulum Ca2+ release events. In addition, there was an increased Na+/Ca2+ exchanger expression in cAF, contributing to an increased Ca2+/membrane potential coupling gain. Together, these factors contributed to AF-promoting atrial delayed afterdepolarizations in AF patients. These findings add to our appreciation of the phenomenon of AF begets AF, indicating that, in addition to the well-established tendency of AF to promote its own persistence by remodeling the reentrant substrate, it can enhance spontaneous ectopic (triggered) activity, which induces reentry.
In the second paper (Harada et al. Circulation. 2012:126;2051-2064), it was shown that transient receptor potential canonical-3 (TRPC3) channels regulate cardiac fibroblast proliferation and differentiation by controlling Ca2+ influx and activating extracellular signal-regulated kinase signaling. TRPC3 expression was increased in patients with chronic AF and various experimental AF models via an NFAT-mediated downregulation of microRNA-26, desuppressing TRPC3 expression. TRPC3 blockade inhibited the development of a vulnerable substrate for AF in a dog model of rapid atrial pacing. Together, these data suggest that TRPC3 plays an important role in structural remodeling in atrial fibrillation and is a novel potential therapeutic target.
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