Early remodeling of perinuclear Ca2+ stores and nucleoplasmic Ca2+ signaling during the development of hypertrophy and heart failure

Senka Ljubojevic, Snjezana Radulovic, Gerd Leitinger, Simon Sedej, Michael Sacherer, Michael Holzer, Claudia Winkler, Elisabeth Pritz, Tobias Mittler, Albrecht Schmidt, Michael Sereinigg, Paulina Wakula, Spyros Zissimopoulos, Egbert Bisping, Heiner Post, Gunther Marsche, Julie B C Bossuyt, Donald M Bers, Jens Kockskämper, Burkert Pieske

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background-A hallmark of heart failure is impaired cytoplasmic Ca 2+ handling of cardiomyocytes. It remains unknown whether specific alterations in nuclear Ca2+ handling via altered excitation- transcription coupling contribute to the development and progression of heart failure. Methods and Results-Using tissue and isolated cardiomyocytes from nonfailing and failing human hearts, as well as mouse and rabbit models of hypertrophy and heart failure, we provide compelling evidence for structural and functional changes of the nuclear envelope and nuclear Ca2+ handling in cardiomyocytes as remodeling progresses. Increased nuclear size and less frequent intrusions of the nuclear envelope into the nuclear lumen indicated altered nuclear structure that could have functional consequences. In the (peri)nuclear compartment, there was also reduced expression of Ca2+ pumps and ryanodine receptors, increased expression of inositol-1,4,5- trisphosphate receptors, and differential orientation among these Ca 2+ transporters. These changes were associated with altered nucleoplasmic Ca2+ handling in cardiomyocytes from hypertrophied and failing hearts, reflected as increased diastolic Ca2+ levels with diminished and prolonged nuclear Ca2+ transients and slowed intranuclear Ca2+ diffusion. Altered nucleoplasmic Ca2+ levels were translated to higher activation of nuclear Ca2+/ calmodulin-dependent protein kinase II and nuclear export of histone deacetylases. Importantly, the nuclear Ca2+ alterations occurred early during hypertrophy and preceded the cytoplasmic Ca2+ changes that are typical of heart failure. Conclusions-During cardiac remodeling, early changes of cardiomyocyte nuclei cause altered nuclear Ca2+ signaling implicated in hypertrophic gene program activation. Normalization of nuclear Ca2+ regulation may therefore be a novel therapeutic approach to prevent adverse cardiac remodeling.

Original languageEnglish (US)
Pages (from-to)244-255
Number of pages12
JournalCirculation
Volume130
Issue number3
DOIs
StatePublished - Jul 15 2014

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Cardiac Myocytes
Hypertrophy
Heart Failure
Nuclear Envelope
Inositol 1,4,5-Trisphosphate Receptors
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Ryanodine Receptor Calcium Release Channel
Histone Deacetylases
Cell Nucleus Active Transport
Transcriptional Activation
Rabbits
Therapeutics

Keywords

  • calcium signaling
  • heart failure
  • nuclear envelope
  • remodeling

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Early remodeling of perinuclear Ca2+ stores and nucleoplasmic Ca2+ signaling during the development of hypertrophy and heart failure. / Ljubojevic, Senka; Radulovic, Snjezana; Leitinger, Gerd; Sedej, Simon; Sacherer, Michael; Holzer, Michael; Winkler, Claudia; Pritz, Elisabeth; Mittler, Tobias; Schmidt, Albrecht; Sereinigg, Michael; Wakula, Paulina; Zissimopoulos, Spyros; Bisping, Egbert; Post, Heiner; Marsche, Gunther; Bossuyt, Julie B C; Bers, Donald M; Kockskämper, Jens; Pieske, Burkert.

In: Circulation, Vol. 130, No. 3, 15.07.2014, p. 244-255.

Research output: Contribution to journalArticle

Ljubojevic, S, Radulovic, S, Leitinger, G, Sedej, S, Sacherer, M, Holzer, M, Winkler, C, Pritz, E, Mittler, T, Schmidt, A, Sereinigg, M, Wakula, P, Zissimopoulos, S, Bisping, E, Post, H, Marsche, G, Bossuyt, JBC, Bers, DM, Kockskämper, J & Pieske, B 2014, 'Early remodeling of perinuclear Ca2+ stores and nucleoplasmic Ca2+ signaling during the development of hypertrophy and heart failure', Circulation, vol. 130, no. 3, pp. 244-255. https://doi.org/10.1161/CIRCULATIONAHA.114.008927
Ljubojevic, Senka ; Radulovic, Snjezana ; Leitinger, Gerd ; Sedej, Simon ; Sacherer, Michael ; Holzer, Michael ; Winkler, Claudia ; Pritz, Elisabeth ; Mittler, Tobias ; Schmidt, Albrecht ; Sereinigg, Michael ; Wakula, Paulina ; Zissimopoulos, Spyros ; Bisping, Egbert ; Post, Heiner ; Marsche, Gunther ; Bossuyt, Julie B C ; Bers, Donald M ; Kockskämper, Jens ; Pieske, Burkert. / Early remodeling of perinuclear Ca2+ stores and nucleoplasmic Ca2+ signaling during the development of hypertrophy and heart failure. In: Circulation. 2014 ; Vol. 130, No. 3. pp. 244-255.
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abstract = "Background-A hallmark of heart failure is impaired cytoplasmic Ca 2+ handling of cardiomyocytes. It remains unknown whether specific alterations in nuclear Ca2+ handling via altered excitation- transcription coupling contribute to the development and progression of heart failure. Methods and Results-Using tissue and isolated cardiomyocytes from nonfailing and failing human hearts, as well as mouse and rabbit models of hypertrophy and heart failure, we provide compelling evidence for structural and functional changes of the nuclear envelope and nuclear Ca2+ handling in cardiomyocytes as remodeling progresses. Increased nuclear size and less frequent intrusions of the nuclear envelope into the nuclear lumen indicated altered nuclear structure that could have functional consequences. In the (peri)nuclear compartment, there was also reduced expression of Ca2+ pumps and ryanodine receptors, increased expression of inositol-1,4,5- trisphosphate receptors, and differential orientation among these Ca 2+ transporters. These changes were associated with altered nucleoplasmic Ca2+ handling in cardiomyocytes from hypertrophied and failing hearts, reflected as increased diastolic Ca2+ levels with diminished and prolonged nuclear Ca2+ transients and slowed intranuclear Ca2+ diffusion. Altered nucleoplasmic Ca2+ levels were translated to higher activation of nuclear Ca2+/ calmodulin-dependent protein kinase II and nuclear export of histone deacetylases. Importantly, the nuclear Ca2+ alterations occurred early during hypertrophy and preceded the cytoplasmic Ca2+ changes that are typical of heart failure. Conclusions-During cardiac remodeling, early changes of cardiomyocyte nuclei cause altered nuclear Ca2+ signaling implicated in hypertrophic gene program activation. Normalization of nuclear Ca2+ regulation may therefore be a novel therapeutic approach to prevent adverse cardiac remodeling.",
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AU - Sedej, Simon

AU - Sacherer, Michael

AU - Holzer, Michael

AU - Winkler, Claudia

AU - Pritz, Elisabeth

AU - Mittler, Tobias

AU - Schmidt, Albrecht

AU - Sereinigg, Michael

AU - Wakula, Paulina

AU - Zissimopoulos, Spyros

AU - Bisping, Egbert

AU - Post, Heiner

AU - Marsche, Gunther

AU - Bossuyt, Julie B C

AU - Bers, Donald M

AU - Kockskämper, Jens

AU - Pieske, Burkert

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N2 - Background-A hallmark of heart failure is impaired cytoplasmic Ca 2+ handling of cardiomyocytes. It remains unknown whether specific alterations in nuclear Ca2+ handling via altered excitation- transcription coupling contribute to the development and progression of heart failure. Methods and Results-Using tissue and isolated cardiomyocytes from nonfailing and failing human hearts, as well as mouse and rabbit models of hypertrophy and heart failure, we provide compelling evidence for structural and functional changes of the nuclear envelope and nuclear Ca2+ handling in cardiomyocytes as remodeling progresses. Increased nuclear size and less frequent intrusions of the nuclear envelope into the nuclear lumen indicated altered nuclear structure that could have functional consequences. In the (peri)nuclear compartment, there was also reduced expression of Ca2+ pumps and ryanodine receptors, increased expression of inositol-1,4,5- trisphosphate receptors, and differential orientation among these Ca 2+ transporters. These changes were associated with altered nucleoplasmic Ca2+ handling in cardiomyocytes from hypertrophied and failing hearts, reflected as increased diastolic Ca2+ levels with diminished and prolonged nuclear Ca2+ transients and slowed intranuclear Ca2+ diffusion. Altered nucleoplasmic Ca2+ levels were translated to higher activation of nuclear Ca2+/ calmodulin-dependent protein kinase II and nuclear export of histone deacetylases. Importantly, the nuclear Ca2+ alterations occurred early during hypertrophy and preceded the cytoplasmic Ca2+ changes that are typical of heart failure. Conclusions-During cardiac remodeling, early changes of cardiomyocyte nuclei cause altered nuclear Ca2+ signaling implicated in hypertrophic gene program activation. Normalization of nuclear Ca2+ regulation may therefore be a novel therapeutic approach to prevent adverse cardiac remodeling.

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