F1 Focus Issue 2nd ECS Workshop 2009 Annexins, targets and calcium-binding proteins in pathology Smolenice, June 3–6, 2009, Slovakia Editors A. Breier, C. W. Heizmann and B. Uhrík F2 Gen. Physiol. Biophys. (2009), 28, Focus Issue, F2 Preface The 2nd ECS Workshop on Annexins, Targets and Calcium-Binding Proteins in Pathology This workshop was held in the beautiful Smolenice castle in Slovakia from June 3-6, 2009 and organized by the European Calcium Society (Claus Heizmann) in cooperation with the Slovak Academy of Sciences (Albert Breier). The village of Smolenice is located in the west of Slovakia, about 60 km from the capital city of Bratislava. The Smolenice castle is located above the village on the foothills of the Carpatian mountains. First documents of the existence of this castle date back to the 13th century. During the Napoleon war the castle de- cayed after the main building and the tower had been destroyed. Reconstruction of the castle was started early in the 20th century. In 1953 the castle was handed over to the Slovak Academy of Sciences (SAS) to become their representative International Congress Center. 65 scientists (mostly young investigators) attended this 2nd ECS workshop; the participants came from 15 different countries including Argentina, Canada, USA, Russia and Poland. The scientific program opened with the keynote lecture of Joseph Metzger (University of Minnesota, Minneapolis) dis- cussing the defective intracellular calcium handling in diastolic heart failure (DHF) and the gene transfer of parvalbumin restoring myocardial performance in DHF. The next day two sessions followed discussing the structures and functions of annexins and their interactions with target proteins with the emphasis on the EF-hand calcium-binding proteins sorcin and S100 proteins. The 3rd day was devoted to the role of the calcium-binding proteins in pathology and their application in clinical di- agnostics with excellent lectures on calcineurin in leukemias, calpain in Alzheimer’s disease, CaBP’s in allergic diseases, S100A4 in tumor growth and metastasis and S100B in psychiatric disorders. The final day was devoted to the calcium-binding proteins ofthe endoplasmatic reticulum under normal and pathological conditions. Highly interesting lectures covered the following topics: Calcium-dependent interplay between ER and multi- drug resistancy, calcium-channels in health and disease, calcium–binding chaperons in the ER, calcium stores in relation to ischemia, and regulation of S100P in cancer cells. An impressing highlight was the very lively poster session of the young investigators. This issue of the Journal “General Physiology and Biophysics” of the Slovak Academy of Sciences, Bratislava, Slovakia contains the papers of the invited speakers. The poster abstracts will be displayed on the ECS web page and on the web page of General Physiology and Biophysics. The organizers are especially grateful to Branislav Uhrik(SAS), the local organizers, and Roland Pochet (General Sec- retary of the ECS) helping in many tasks, turning this workshop into a memorable success. More information with pictures of the lectures, poster session and of the social activities are found on our ECS webpage (www.ulb.ac.be/assoc/ecs) and the upcoming ECS Newsletter. Summarizing I can say that this was an excellent and a well attended workshop and we are looking forward to the 11th European Symposium on Calcium which will be organized by Jacek Kuznicki and his team on the 5th-8th September 2010 in Warsaw, Poland. Claus W. Heizmann University of Zürich, Zürich, Switzerland E-mail: [email protected] Disclosure statement. The editors of this Focus Issue are members of the Editorial Board of General Physiology and Biophysics and have no financial interests related to the material in the manuscript nor to the participation in the 2nd ECS Workshop. Gen. Physiol. Biophys. (2009), 28, Focus Issue, F3–F6 F3 Review Parvalbumin: Targeting calcium handling in cardiac diastolic dysfunction Wang Wang, Joshua Martindale and Joseph M. Metzger Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA, 55455 Abstract. Diastolic heart failure (DHF) is a clinical syndrome characterized by depressed myocardial relaxation performance and poor ventricular refilling. Defective intracellular calcium (Ca2+) handling underlies one of the fundamental mechanisms of DHF. Manipulating the content and function of Ca2+ handling proteins in the heart has been the focus of intense study to develop effective therapies for DHF patients. Parvalbumin (Parv), a skeletal muscle Ca2+ binding protein, has been shown to facilitate myocardial relaxation both in vitro and in vivo. Parv acts as a unique “delayed” Ca2+ buffer and facilitates Ca2+ sequestration from cytosol. Here, we summarize studies employing gene transfer of Parv in cultured adult cardiac myocytes and in vivo to redress depressed diastolic function. By targeting defects in cardiac Ca2+ handling, Parv represents a promising therapeutic candidate for alleviating diastolic dysfunction in DHF. Key words: Parvalbumin — Calcium handling — Diastolic heart failure Cardiac diastolic dysfunction and calcium handling genesis of DHF. Studies in human and animals suggest that delayed Ca2+ sequestration is an important factor leading Congestive heart failure (CHF) is a clinical syndrome of to slowed Ca2+ transient decay and myocyte relaxation as compromised pumping function of the heart. Diastolic well as elevated diastolic Ca2+ levels (Houser et al. 2000; Zile dysfunction can dominate the early phase of CHF before and Brutsaert 2002). significant decrease in cardiac output occurs. Moreover, Normal cardiac function relies on seamlessly coupled about 40% of the CHF patients experience isolated diastolic processes of myocyte contraction and relaxation driven by heart failure (DHF) in the absence of significant systolic oscillations in cytosolic Ca2+. Timely control of intracellular dysfunction (Chinnaiyan et al. 2007; Owan and Redfield Ca2+ levels requires the released Ca2+ be removed promptly. 2005). Importantly, DHF is more prominent among elderly The decay of the Ca2+ transient involves sequential proc- population (Kitzman et al. 2001). Mechanistically, DHF is esses including Ca2+ dissociation from troponin C, Ca2+ a chronic condition that involves one or more pathologi- reuptake into sarcoplasmic reticulum (SR) by phospholam- cal abnormalities of the myocardium, including impaired ban (PLN) regulated sarcoplasmic (endoplasmic) reticulum cardiac myocyte relaxation, increased ventricular wall stiff- Ca2+ ATPase (SERCA) and Ca2+ export through Na+/Ca2+ ness / thickness and restricted pericardial structures. These exchanger (NCX). The function and abundance of these key pathological conditions are often caused by dysregulated Ca2+ cycling molecules are known to be altered during DHF. intracellular Ca2+ handling, myocyte hypertrophy, extracel- Such alterations include decreased SERCA2a expression and lular collagen deposition, elevated afterload, and confined activity, decreased SERCA2a/PLN ratio, up-regulated NCX ventricular wall movements (Zile and Brutsaert 2002). and increased ryanodine receptor (RyR) open probability Defective Ca2+ removal is a key factor underlying the patho- and Ca2+ leak (Arai et al. 1994; Houser et al. 2000; Wehrens 2+ et al. 2005). These changes ultimately lead to delayed Ca 2+ Correspondence to: Joseph M. Metzger, Department of Integrative removal, diminished Ca storage and release, elevated 2+ Biology and Physiology, 6-125 Jackson Hall, 321 Church Street SE, resting cytosolic Ca , and increased vulnerability to ar- Minneapolis, MN 55455, USA rhythmia (Minamisawa et al. 2004; Molkentin 2005; Pieske E-mail: [email protected] et al. 1999). F4 Wang et al. A direct gene transfer approach that manipulates Ca2+ Parv’s effects on cardiac performance. Parv dramatically regulating proteins has been used to develop new thera- increases the rate of Ca2+ transient decay and accelerates pies for diastolic dysfunction. Promising results in rodents myocyte mechanical relaxation in a dose-dependent man- have been obtained from studies such as overexpression of ner in normal adult cardiac myocytes from rodents and SERCA2a, sorcin and S100A1 or depletion of PLN, in which canines (Coutu et al. 2004; Hirsch et al. 2004; Rodenbaugh diastolic and systolic dysfunction are improved (del Monte et al. 2007; Wahr et al. 1999). Parv expressing myocytes also and Hajjar 2003; Hoshijima 2005; Minamisawa et al. 1999; retain their ability to fully respond to β-adrenergic stimula- Most et al. 2004). However, several critical issues remain tion (Hirsch et al. 2004). In vivo gene transfer of Parv via unsolved regarding the effectiveness of targeting endog- direct intra-myocardial injection achieves physiologically enous Ca2+ cycling process in DHF. For instance, NCX has relevant concentrations of Parv in vivo (Coutu et al. 2004; been shown to be elevated in HF, but experimental NCX Michele et al. 2004; Szatkowski et al. 2001). Parv express- overexpression exerts either beneficial or deleterious effects ing hearts exhibit increased relaxation speed measured by (Schillinger et al. 2000; Terracciano et al. 1998). The results working heart strip preparation, in vivo micromanometry of sorcin gene transfer in regulating contractility, relaxation and echocardiography (Szatkowski et al. 2001). In aged rats, and SR Ca2+ content are conflicting among studies (Seidler in vivo Parv gene transfer