1. Early Remodeling of Perinuclear Ca2+ Stores and Nucleoplasmic Ca2+ Signaling During the Development of Hypertrophy and Heart Failure
- Author
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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, Bers, Donald M, Kockskämper, Jens, and Pieske, Burkert
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,Cardiovascular ,Genetics ,Heart Disease ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Calcium ,Calcium Signaling ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Cardiomegaly ,Cell Nucleus ,Disease Models ,Animal ,Electric Stimulation ,Female ,Heart Failure ,Histone Deacetylases ,Humans ,Inositol 1 ,4 ,5-Trisphosphate Receptors ,Male ,Mice ,Mice ,Inbred C57BL ,Middle Aged ,Myocytes ,Cardiac ,Rabbits ,Ventricular Remodeling ,calcium signaling ,heart failure ,nuclear envelope ,remodeling ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Public Health and Health Services ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences ,Sports science and exercise - Abstract
BackgroundA 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 resultsUsing 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.ConclusionsDuring 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.
- Published
- 2014