Enhanced nucleoplasmic Ca2+signaling in ventricular myocytes from young hypertensive rats.
Arterial hypertension causes left ventricular (LV) myocyte hypertrophy. Alterations in nuclear Ca2+may be involved in regulation of histone acetylation, transcription and hypertrophy. Regulation of nuclear Ca2+in hypertension, however, is unknown. Therefore, we elucidated cellular mechanisms underlying nuclear Ca2+regulation in LV myocytes from hypertensive versus normotensive rats and evaluated possible consequences for Ca2+-dependent regulation of histone acetylation. LV myocytes and myocyte nuclei were isolated from young spontaneously hypertensive rats (SHR) shortly after development of hypertension. Normotensive Wistar-Kyoto rats (WKY) served as controls. Cytoplasmic and nucleoplasmic Ca2+transients (CaTs) were imaged simultaneously using linescan confocal microscopy and Fluo-4. LV myocytes and nuclei from SHR exhibited hypertrophy. Cytoplasmic and nucleoplasmic CaTs were increased in SHR. The increase in nucleoplasmic Ca2+, however, exceeded the increase in cytoplasmic Ca2+, indicating enhanced nuclear Ca2+signaling in SHR. Ca2+load of sarcoplasmic reticulum and perinuclear Ca2+stores was also increased in SHR, while fractional release from both stores remained unchanged. Intranuclear Ca2+propagation was accelerated in SHR, associated with preserved density of nuclear envelope invaginations and elevated nuclear expression of nucleoporins and SR-Ca2+-ATPase, SERCA2a. Nuclear Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIδ) expression was elevated and histone deacetylases exhibited redistribution from nucleus to cytosol associated with increased histone acetylation in SHR. Thus, in early hypertension, there is remodeling of nuclear Ca2+handling resulting in enhanced nuclear Ca2+signaling. Enhanced nuclear Ca2+signaling, in turn, increases nuclear localization and activity of CaMKIIδ driving nuclear export of histone deacetylases and increased histone acetylation.
Institute of Pharmacology and Clinical Pharmacy, Biochemical and Pharmacological Center (BPC) Marburg, University of Marburg, Karl-von-Frisch-Str. 1, D-35032 Marburg, Germany.
Jelena
J
Plačkić
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Albertstr. 25, D-79104 Freiburg, Germany.
Sebastian
S
Preissl
Institute of Pharmacology and Clinical Pharmacy, Biochemical and Pharmacological Center (BPC) Marburg, University of Marburg, Karl-von-Frisch-Str. 1, D-35032 Marburg, Germany.
Yulia
Y
Nikonova
Institute of Pharmacology and Clinical Pharmacy, Biochemical and Pharmacological Center (BPC) Marburg, University of Marburg, Karl-von-Frisch-Str. 1, D-35032 Marburg, Germany.
Florentina
F
Pluteanu
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Albertstr. 25, D-79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Schänzlestr. 18, D-79104 Freiburg, Germany.
Lutz
L
Hein
Institute of Pharmacology and Clinical Pharmacy, Biochemical and Pharmacological Center (BPC) Marburg, University of Marburg, Karl-von-Frisch-Str. 1, D-35032 Marburg, Germany. Electronic address: jens.kockskaemper@staff.uni-marburg.de.
Jens
J
Kockskämper
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000166:cytology* / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006973:Hypertension / Q000209:etiology / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
D017871:Calcium-Calmodulin-Dependent Protein Kinases; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases; D002118:Calcium
Calcium; Histone acetylation; Hypertension; Hypertrophy; Nucleus