Intracellular Dyssynchrony of Diastolic Cytosolic [Ca2+] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure
Intracellular Dyssynchrony of Diastolic Cytosolic [Ca2+] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure
复制标题
DOI：
10.1161/circresaha.113.300895
复制
发表时间：
2013-08-16
影响因子：
20.1
通讯作者：
Heinzel, Frank R.
中科院分区：
文献类型：
--
作者：
Hohendanner, Felix;Ljubojevic, Senka;Heinzel, Frank R.
基本原理：同步释放的Ca 2+到细胞溶质在每个心动周期确定cardiomyocyte contraction.Objective：我们研究了同步的细胞溶质[Ca 2 +]衰减在cardiomyoleandimpact of cardiac remodel.Methods和Results：Local cytosolic [Ca 2 +] transients（1-mu m intervals）被记录在小鼠，猪，和人心室单个心肌细胞。我们根据局部衰变时间常数（TAU（局部））确定了缓慢（slowCaR）和快速（fastCaR）[Ca 2 +]衰变的细胞内区域。TAU（局部）的SD作为不同步性的量度与局部Ca 2+释放的幅度或时间无关。在慢CaR中，用forskolin或istaroxime刺激肌浆网Ca 2 + ATP酶加速，用cyclopiazonic acid抑制，显著减慢TAU（局部），从而改变了TAU（局部）和整体[Ca 2 +]衰减（TAU（全局））的SD之间的关系。Na+/Ca 2+交换抑制剂SEA 0400延长慢CaR和快CaR的TAU（局部）相似。FastCaR与线粒体密度增加相关，对线粒体Ca 2+单向转运体阻断剂Ru 360更敏感。TAU（局部）的变化在猪和人心肌细胞中较高，并且随着刺激频率（2 Hz）的增加而升高。TAU（局部）与局部肌节再伸长相关。在小鼠与心肌肥厚后，横向主动脉缩窄，在猪慢性心肌缺血，并在终末期人类心力衰竭，TAU（本地）的变化增加和相关的心肌细胞肥大和增加线粒体density.Conclusions：在心肌细胞，胞浆[Ca 2 +]衰减调节本地和相关的局部肌节relengthening。心脏重塑和终末期心力衰竭中细胞内[Ca 2 +]衰减不同步提示细胞收缩功能障碍的新机制。
Rationale: Synchronized release of Ca2+ into the cytosol during each cardiac cycle determines cardiomyocyte contraction.Objective: We investigated synchrony of cytosolic [Ca2+] decay during diastole and the impact of cardiac remodeling.Methods and Results: Local cytosolic [Ca2+] transients (1-mu m intervals) were recorded in murine, porcine, and human ventricular single cardiomyocytes. We identified intracellular regions of slow (slowCaR) and fast (fastCaR) [Ca2+] decay based on the local time constants of decay (TAU(local)). The SD of TAU(local) as a measure of dyssynchrony was not related to the amplitude or the timing of local Ca2+ release. Stimulation of sarcoplasmic reticulum Ca2+ ATPase with forskolin or istaroxime accelerated and its inhibition with cyclopiazonic acid slowed TAU(local) significantly more in slowCaR, thus altering the relationship between SD of TAU(local) and global [Ca2+] decay (TAU(global)). Na+/Ca2+ exchanger inhibitor SEA0400 prolonged TAU(local) similarly in slowCaR and fastCaR. FastCaR were associated with increased mitochondrial density and were more sensitive to the mitochondrial Ca2+ uniporter blocker Ru360. Variation in TAU(local) was higher in pig and human cardiomyocytes and higher with increased stimulation frequency (2 Hz). TAU(local) correlated with local sarcomere relengthening. In mice with myocardial hypertrophy after transverse aortic constriction, in pigs with chronic myocardial ischemia, and in end-stage human heart failure, variation in TAU(local) was increased and related to cardiomyocyte hypertrophy and increased mitochondrial density.Conclusions: In cardiomyocytes, cytosolic [Ca2+] decay is regulated locally and related to local sarcomere relengthening. Dyssynchronous intracellular [Ca2+] decay in cardiac remodeling and end-stage heart failure suggests a novel mechanism of cellular contractile dysfunction.