Senka Ljubojevic1, Snjezana Radulovic1, Gerd Leitinger1, Simon Sedej1, Michael Sacherer1, Michael Holzer1, Claudia Winkler1, Elisabeth Pritz1, Tobias Mittler1, Albrecht Schmidt1, Michael Sereinigg1, Paulina Wakula1, Spyros Zissimopoulos1, Egbert Bisping1, Heiner Post1, Gunther Marsche1, Julie Bossuyt1, Donald M Bers1, Jens Kockskämper1, Burkert Pieske2. 1. 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.). 2. 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.
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. 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 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.
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. 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 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.
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