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, Pieske Burkert
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.).
Circulation. 2014 Jul 15;130(3):244-55. doi: 10.1161/CIRCULATIONAHA.114.008927. Epub 2014 Jun 13.
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.
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.
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.
心力衰竭的一个标志是心肌细胞胞质钙（Ca2+）处理受损。通过改变兴奋-转录偶联导致的核Ca2+处理的特定改变是否有助于心力衰竭的发生和发展尚不清楚。
使用来自非衰竭和衰竭人类心脏的组织和分离的心肌细胞，以及肥大和心力衰竭的小鼠和兔子模型，我们提供了令人信服的证据，表明随着重塑进展，心肌细胞核膜和核Ca2+处理存在结构和功能变化。核大小增加以及核膜向核腔的侵入频率降低表明核结构改变，这可能会产生功能后果。在（核）周区域，Ca2+泵和兰尼碱受体的表达也减少，肌醇-1,4,5-三磷酸受体的表达增加，并且这些Ca2+转运蛋白之间存在不同的取向。这些变化与肥大和衰竭心脏的心肌细胞核质Ca2+处理改变有关，表现为舒张期Ca2+水平升高，核Ca2+瞬变减少和延长，以及核内Ca2+扩散减慢。核质Ca2+水平的改变转化为核Ca2+/钙调蛋白依赖性蛋白激酶II的更高激活和组蛋白脱乙酰酶的核输出。重要的是，核Ca2+改变在肥大早期发生，并且先于心力衰竭典型的胞质Ca2+变化。
在心脏重塑过程中，心肌细胞核的早期变化导致核Ca2+信号改变，这与肥大基因程序激活有关。因此，核Ca2+调节的正常化可能是预防不良心脏重塑的一种新的治疗方法。
