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Early changes of Ca-mediated transcription in heart failure

Early changes of Ca-mediated transcription in heart failure

Senka Holzer (ORCID: 0000-0001-6994-9976)
  • Grant DOI 10.55776/T607
  • Funding program Hertha Firnberg
  • Status ended
  • Start October 1, 2013
  • End October 31, 2017
  • Funding amount € 211,830
  • Project website
  • E-mail

Disciplines

Biology (15%); Medical-Theoretical Sciences, Pharmacy (85%)

Keywords

    Heart Failure, Nuclear Calcium, Hypertrophy, FRET imaging, Excitation-Transcription Coupling, CaMKII

Abstract Final report

Heart failure is a leading cause of death in the developed countries partly as a result of the ageing population and a lack of curative therapies. In heart failure, intracellular Ca2+ homeostasis is altered and it has been implicated in the activation of hypertrophic signalling cascades ultimately culminating in overt heart failure phenotype. Recent studies showed that elements of signaling pathways involved in the development of hypertrophy, including the Ca2+-dependent regulators of transcriptions, can have a distinct localization towards perinuclear regions of the cell. Together with the observation that nuclear envelope can control the local Ca2+ levels in its close proximity and in the nucleoplasm, it represents an attractive possible regulatory mechanism involved in the development of heart failure. However, almost nothing is known about the subcellular organization and the origin of increased intracellular Ca2+ fluxes that initiate Ca2+-dependent maladaptive hypertrophic gene expression in (peri)nuclear regions. Our preliminary data provide strong evidence for a structural and functional remodelling of the nuclear envelope at the very early phase of cardiac hypertrophy in an animal model of pressure overload and as a proof-of-principle in failing human hearts. This in turn, led to alterations of nucleoplasmic Ca2+ concentration, [Ca 2+], with an onset so early that it is likely to be via excitation-transcription coupling involved in the further progression of hypertrophy and heart failure. In the proposed project we will pursue the hypothesis that various triggers (i.e. endothelin-1 and high stimulation frequency) that selectively increase nucleoplasmic [Ca 2+] with little effect on global cytoplasmic [Ca 2+] causes due to the structural and functional remodelling of nuclear envelope and perinuclear regions an even higher increase in local nucleoplasmic [Ca 2+] in cardiomyocytes from an animal model of pressure-overload and human hearts at the early stage of hypertrophy compared to control hearts. We also want to show that high nuclear [Ca 2+] is an essential trigger for increased transcription and the initiation of the hypertrophic gene program in (peri)nuclear regions. To address this, a need for the powerful imaging technique such as FRET imaging emerged. We therefore established a cooperation with the leading European laboratory for FRET imaging in cardiomyocytes. The results of this project should set a basis for the new concept of heart failure development and progression with the nucleoplasmic Ca2+ as a key player for future research. Better understanding of the organization of hypertrophic signalling cascades should lead to the development of novel therapeutic strategies that can by acting on a limited subset of downstream targets improve efficacy and minimize off-target effects.

Hypertrophy and heart failure are severe and widespread cardiac diseases associated with increased morbidity and mortality. Heart failure currently affects more than 200,000 people in Austria with an increasing tendency and is one of the most important causes of reduced physical and mental performance. Restrictions in everyday life and frequent visits to hospital reduce the quality of life of those affected and contribute to a major socio-economic burden of the disease. The development of heart failure features a large number of changes in the heart, commonly termed as cardiac remodeling. Remodeling is initially characterized by thickening of the heart muscle hypertrophy which may help when an increased pumping work is needed. However, on the long run it leads to structural and functional damage of the heart and the progression of the disease. The cellular mechanisms underlying the cardiac remodeling are largely unknown and they were the main focus of this research project. The specific aim of the project was to examine how the calcium homeostasis (calcium is the main regulator of cardiac contraction) is altered in heart cells of patients with heart failure. For this purpose, cardiac cells were obtained from explanted hearts and examined for excitatory conduction and gene expression by means of biophysical methods. Our analyses showed surprising results. We were able to demonstrate for the first time that changes in calcium cycling within the heart cell originate in the nucleus. These changes lead to a change in gene expression, which lead to a further disturbance of the calcium homeostasis. Furthermore, we were able to replicate these changes in animal models and thus confirm the relationship between altered calcium dependent-gene expression and heart failure. In conclusion, the present work features a new paradigm for cardiac hypertrophy and failure, in which early remodeling of calcium homeostasis in the cell nucleus is an important factor for the development and progression of this common and severe cardiac disease. Normalization of impaired calcium cycling in the nucleus may therefore be a novel therapeutic approach for the prevention of adverse cardiac remodeling. The aim of our further studies is to identify in more details the machinery involved in the regulation of nuclear calcium homeostasis in order to develop innovative treatment strategies, that can by acting on a limited subset of downstream targets improve efficacy and minimize off-target effects.

Research institution(s)
  • Medizinische Universität Graz - 100%
International project participants
  • Manuela Zaccolo, The University of Oxford - United Kingdom

Research Output

  • 112 Citations
  • 2 Publications
  • 1 Policies
  • 1 Disseminations
  • 6 Scientific Awards
  • 2 Fundings
Publications
  • 2014
    Title Early Remodeling of Perinuclear Ca2+ Stores and Nucleoplasmic Ca2+ Signaling During the Development of Hypertrophy and Heart Failure
    DOI 10.1161/circulationaha.114.008927
    Type Journal Article
    Author Ljubojevic S
    Journal Circulation
    Pages 244-255
    Link Publication
  • 2015
    Title Nuclear Calcium in Cardiac Myocytes
    DOI 10.1097/fjc.0000000000000174
    Type Journal Article
    Author Ljubojevic S
    Journal Journal of Cardiovascular Pharmacology
    Pages 211-217
    Link Publication
Policies
  • 2013 Link
    Title Elected nucleus member of the "Scientists of Tomorrow" section of the European Society of Cardiology
    Type Participation in a guidance/advisory committee
    Link Link
Disseminations
  • 0 Link
    Title Interview for national newspaper "Der Standard"
    Type A press release, press conference or response to a media enquiry/interview
    Link Link
Scientific Awards
  • 2017
    Title Invited speaker at the European Society of Cardiology Congress 2017
    Type Personally asked as a key note speaker to a conference
    Level of Recognition Continental/International
  • 2015
    Title Invited speaker at the European Society of Cardiology Congress 2015
    Type Personally asked as a key note speaker to a conference
    Level of Recognition Continental/International
  • 2015
    Title Sanofi Aventis Prize
    Type Research prize
    Level of Recognition Regional (any country)
  • 2014
    Title Invited speaker at the Winter Heart Failure Meeting 2014
    Type Personally asked as a key note speaker to a conference
    Level of Recognition Continental/International
  • 2014
    Title Invited speaker at the Frontiers in Cardiovascular Biology 2014
    Type Personally asked as a key note speaker to a conference
    Level of Recognition Continental/International
  • 2014
    Title Invited speaker at the European Society of Cardiology Congress 2014
    Type Personally asked as a key note speaker to a conference
    Level of Recognition Continental/International
Fundings
  • 2013
    Title Visiting Scientists Program
    Type Fellowship
    Start of Funding 2013
    Funder Bank Austria
  • 2015
    Title Mobility Scholarship for families
    Type Fellowship
    Start of Funding 2015
    Funder Medical University of Graz

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