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Structural and Functional Differences Between Cardiomyocytes from Right and Left Ventricles in Health and Disease

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Structural and Functional Differences Between Cardiomyocytes from Right and Left Ventricles in Health and Disease DEPARTMENT OF _SURGERY, DENTISTRY, PAEDIATRICS AND GYNAECOLOGY_ PHD SCHOOL ___LIFE AND HEALTH SCIENCES___ PHD IN ____________CARDIOVASCULAR SCIENCE_________ With funding by ____________UNIVERSITY OF VERONA___________ CYCLE / YEAR of initial enrolment ____XXXII (2016)_______ PHD THESIS TITLE Structural and functional differences between cardiomyocytes from right and left ventricles in health and disease S.S.D. (Disciplinary Sector) ___ MED/11__ Coordinator: Prof. GIOVANNI BATTISTA LUCIANI Signature ___________________________ Tutor: Prof. GIUSEPPE FAGGIAN Signature __________________________ Tutor: Prof. JULIA GORELIK Signature __________________________ Tutor: Prof. MICHELE MIRAGOLI Signature __________________________ PhD candidate: ROMAN MEDVEDEV Signature_____________________________ This work is licensed under a Creative Commons Attribution-Non Commercial- NoDerivs 3.0 Unported License, Italy. To read a copy of the licence, visit the web page: http://creativecommons.org/licenses/by-nc-nd/3.0/ Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. NonCommercial — You may not use the material for commercial purposes. NoDerivatives — If you remix, transform, or build upon the material, you may not distribute the modified material. STRUCTURAL AND FUNCTIONAL DIFFERENCES BETWEEN CARDIOMYOCYTES FROM RIGHT AND LEFT VENTRICLES IN HEALTH AND DISEASE Roman Medvedev PhD thesis Verona, ISBN 12324-5678-910 Abstract Several disorders including pulmonary hypertension (PH) and heart failure (HF) could lead to right ventricle (RV) hypertrophy and failure. RV failure is one of the most important prognostic factors for morbidity and mortality in these disorders. However, there is still no therapy to prevent the RV hypertrophy in PH. Treatments developed for the left ventricle (LV) failure do not improve the survival in patients with RV failure probably due to the significant differences in the chambers physiology and hemodynamic function. A better understanding of the cellular and molecular mechanisms of RV hypertrophy is needed. Our focus lies into the alterations of cellular microarchitecture that promotes functional changes in Ca2+ handling. Recently our group showed that reorganisation of the transverse-axial tubular system (TATS) in HF are of particular importance for Ca2+ mishandling and contractile impairment of failing cells. Rationale: This study aims to establish the differences in membrane organisation of Ca2+ handling between healthy RV and LV myocytes, and to investigate the remodelling of RV during disease. Specifically, the objectives are: (1) To study the membrane organisation of RV and LV myocytes by revealing the surface topography using Scanning Ion Conductance Microscopy and by studying the TATS using confocal microscopy. (2) To assess the contraction and Ca2+ transients in RV and LV myocytes. (3) To determine the spatial distribution and properties of single L-type Ca2+ channels (LTCC) in RV myocytes using “smart patch clamp” technique. (4) To describe the changes occurring in the RV and LV in the two disease rat models: PH induced by monocrotaline injection and HF induced by chronic myocardial infarction (MI). This thesis showed that in healthy samples the TATS of RV myocytes has a different organization as compared to LV. Two main Ca2+ channels for the excitation-contraction coupling: LTCC and ryanodine receptors (RyR) were studied by immunofluorescence staining. The density of LTCC was lower in RV than in LV myocytes. However, the density of RyR was similar between the chambers. Contraction duration was longer in RV than in LV myocytes. The distribution of 3 functional LTCCs in RV myocytes was uniform along the cell surface, in contrast to LV myocytes, where LTCCs were primarily located in the T-tubules. Secondly, PH rats showed a reduction of the conduction velocity anisotropy throughout the RV as well as prolongation of the refractoriness of the tissue. The hypertrophy of RV myocytes in PH was accompanied by the reduction of the TATS organisation. The amplitude of contraction of RV PH myocytes was higher, the activation of Ca2+ transients was more desynchronised than in controls, and the rate of spontaneous Ca2+ activity was significantly elevated. Functionally, in PH the open probability (Po) of LTCC located in the T-tubules was significantly higher. On the other hand, PH LV myocytes had preserved TATS but still showed prolonged Ca2+ transients that could influence increased refractoriness of LV tissue. Thirdly, by studying RV myocytes from the MI model, a significant hypertrophy was found, accompanied by a reduction of TATS organisation. The study reports a prolongation of Ca2+ transients with more frequent local Ca2+ waves in MI versus control RV myocytes. Higher Po of LTCCs was shown in MI RV myocytes could be associated with the PKA-mediated phosphorylation. In summary, RV myocytes have a lower TATS organisation than LV myocytes probably related to the lower workload of the RV chamber. Consequently, RV myocytes present several differences with LV myocytes, including changes in the Ca2+ handling or a more uniform distribution of LTCC on the membrane. Diseases induce reduction of TATS and Ca2+ mishandling in both chambers. Due to the intrinsic differences of RV versus LV myocytes, the RV could be more prone to pathological events in early stages of the diseases, which should be investigated further. 4 Publications (submitted or expected from this work) Medvedev RY, Sanchez-Alonso J.L., Alvarez-Laviada A., Rossi S., Dries E., Abdul-Salam V.B., Wojciak-Stothard D., Miragoli M., Faggian G., Gorelik J. Nanoscale study of calcium handling remodelling in right ventricular cardiomyocytes following pulmonary hypertension. (In preparation, to be submitted to Hypertension). Medvedev RY, Sanchez-Alonso J.L., Pagiatakis C, Miragoli M, Faggian G. Gorelik J. Local hyperactivation of L-type Ca2+ channels and spontaneous Ca2+ sparks in the right ventricle after membrane disorganisation in heart failure. (In preparation, to be submitted to Scientific Reports.) Medvedev RY, Sanchez-Alonso JL, Alvarez A., Miragoli M, Faggian G. Gorelik J. Right ventricular myocytes have less organized membrane structures and different localization of L-type Ca2+ channels compared to myocytes from left ventricle. Journal of molecular and cellular cardiology, Issue 120 (Supplement 1) 2018. Presentations 1. “Differences in localisation of calcium channels and membrane structures in right and left ventricular myocytes” Poster and Oral presentation, International Society for Heart Research, Amsterdam, 2018 2. “Structural and functional differences between cardiomyocytes from right and left ventricles in health and disease.” Departmental presentation in Imperial College London, 30 January 2019. 5 Declaration: This thesis resents my own work unless otherwise indicated within the text. This work has not been submitted at any other academic institution. Roman Medvedev, Verona, September 2019 6 Acknowledgments I want to thank my supervisor Prof. Giuseppe Faggian for providing me the possibility to make this work and for his great interest and supervising of all my studies. I want to thank my second supervisor, Prof. Julia Gorelik, for encouraging me to microdomain world and providing the possibility to make this work, whose enormous energy and patience helped a lot during all my studies. I am very grateful to Dr. Michele Miragoli who was my co-supervisor at Humanitas University and University of Parma for providing me the possibility to learn a lot about different methodologies and helpful conversations regarding my project. I want to say many thanks to Dr. Sanchez-Alonso who introduced me to the world of electrophysiology and who provided me great discussions and help in building up the story of the work. His support and enormous energy helped to finish this work. I want to thank all the members of Prof. Gorelik's group at Imperial College. Dr. Ivan Diakonov, Dr. Anita Alvarez-Laviada, Dr. Peter Wright, and all the Ph.D. students. Thank you for helping me to settle down when I first visited London and started to work in the laboratory. I am very thankful Mr. Peter O’Gara for his technical support in cell isolations. I want to thank my colleagues from the Humanitas Research institute: Dr. Marta Mazzola, Dr. Silvia Crasto, Mr. Fernando Hall, Dr. Cristina Pagiatakis, and Dr. Veronica Larcher for a great company in Milan and your nice support for me. I want to thank Dr. Tilo Schorn from Imaging Unit in Humanitas Research Institute for his big help with super-resolution STED microscopy. I am very grateful for my colleagues: Mr. Francesco Lo Muzio, Mr. Giacomo Rozzi, Dr. Cristina Caffara, Ms. Amparo Guerrero, and other members of Dr. Michele Miragoli group in Parma for great scientific discussions during the work and funny meeting after it. Lastly, I want to thank my family and friends who supported me all the time and taught me never to give up. 7 List of acronyms AC Adenylyl cyclase AF Atrial fibrillation AKAP79 A-kinase anchoring protein ALC1 Atrial myosin light chain 1 ANOVA Analysis of variance AP Action potential APD Action potential duration A-tubule Axial tubule AV Atrioventricular node AVN Atrioventricular node BayK BayK8644 CaM Calmodulin CaMKII Ca2+/calmodulin-dependent protein kinase II cAMP Cyclic AMP Cav3 Caveolin3 Cavα1C, Cav1.2 α subunit of L-type Ca2+ channels Cavα2/δ α2/δ
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