title: Early remodeling of perinuclear Ca2+ stores and nucleoplasmic Ca2+ signaling during the development of hypertrophy and heart failure.
abstract: BACKGROUND
  A hallmark of heart failure is impaired cytoplasmic Ca(2+) handling of cardiomyocytes. It remains unknown whether specific alterations in nuclear Ca(2+) handling via altered excitation-transcription coupling contribute to the development and progression of heart failure.
  
  
  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 Ca(2+) 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 Ca(2+) 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 Ca(2+) handling in cardiomyocytes from hypertrophied and failing hearts, reflected as increased diastolic Ca(2+) levels with diminished and prolonged nuclear Ca(2+) transients and slowed intranuclear Ca(2+) diffusion. Altered nucleoplasmic Ca(2+) levels were translated to higher activation of nuclear Ca(2+)/calmodulin-dependent protein kinase II and nuclear export of histone deacetylases. Importantly, the nuclear Ca(2+) alterations occurred early during hypertrophy and preceded the cytoplasmic Ca(2+) changes that are typical of heart failure.
  
  
  CONCLUSIONS
  During cardiac remodeling, early changes of cardiomyocyte nuclei cause altered nuclear Ca(2+) signaling implicated in hypertrophic gene program activation. Normalization of nuclear Ca(2+) regulation may therefore be a novel therapeutic approach to prevent adverse cardiac remodeling.
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Senka
authors.initials: S
authors.lastname: Ljubojevic
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Snjezana
authors.initials: S
authors.lastname: Radulovic
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Gerd
authors.initials: G
authors.lastname: Leitinger
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Simon
authors.initials: S
authors.lastname: Sedej
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Michael
authors.initials: M
authors.lastname: Sacherer
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Michael
authors.initials: M
authors.lastname: Holzer
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Claudia
authors.initials: C
authors.lastname: Winkler
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Pritz
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Tobias
authors.initials: T
authors.lastname: Mittler
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Albrecht
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Michael
authors.initials: M
authors.lastname: Sereinigg
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Paulina
authors.initials: P
authors.lastname: Wakula
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Spyros
authors.initials: S
authors.lastname: Zissimopoulos
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Egbert
authors.initials: E
authors.lastname: Bisping
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Heiner
authors.initials: H
authors.lastname: Post
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Julie
authors.initials: J
authors.lastname: Bossuyt
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.).
authors.forename: Jens
authors.initials: J
authors.lastname: Kockskämper
authors.affiliation: From the Department of Cardiology (S.L., S.R., S.S., M. Sacherer, C.W., T.M., A.S., P.W., E.B., H.P., B.P.), Institute of Cell Biology, Histology and Embryology (G.L., E.P.), Institute of Experimental and Clinical Pharmacology (M.H., G.M.), and Division of Transplantation Surgery (M. Sereinigg), Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria (S.L., S.S., P.W., E.B., B.P.); Department of Pharmacology, University of California, Davis, CA (S.L., J.B., D.M.B.); Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (S.Z.); and Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany (J.K.). burkert.pieske@medunigraz.at jens.kockskaemper@staff.uni-marburg.de.
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002467:Cell Nucleus / Q000378:metabolism*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005260:Female; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006655:Histone Deacetylases; D002118:Calcium
keywords: calcium signaling; heart failure; nuclear envelope; remodeling