Sadredini Mani, Danielsen Tore Kristian, Aronsen Jan Magnus, Manotheepan Ravinea, Hougen Karina, Sjaastad Ivar, Stokke Mathis Korseberg
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
PLoS One. 2016 Apr 20;11(4):e0153887. doi: 10.1371/journal.pone.0153887. eCollection 2016.
Abnormal cellular Ca2+ handling contributes to both contractile dysfunction and arrhythmias in heart failure. Reduced Ca2+ transient amplitude due to decreased sarcoplasmic reticulum Ca2+ content is a common finding in heart failure models. However, heart failure models also show increased propensity for diastolic Ca2+ release events which occur when sarcoplasmic reticulum Ca2+ content exceeds a certain threshold level. Such Ca2+ release events can initiate arrhythmias. In this study we aimed to investigate if both of these aspects of altered Ca2+ homeostasis could be found in left ventricular cardiomyocytes from rats with different states of cardiac function six weeks after myocardial infarction when compared to sham-operated controls. Video edge-detection, whole-cell Ca2+ imaging and confocal line-scan imaging were used to investigate cardiomyocyte contractile properties, Ca2+ transients and Ca2+ waves. In baseline conditions, i.e. without beta-adrenoceptor stimulation, cardiomyocytes from rats with large myocardial infarction, but without heart failure, did not differ from sham-operated animals in any of these aspects of cellular function. However, when exposed to beta-adrenoceptor stimulation, cardiomyocytes from both non-failing and failing rat hearts showed decreased sarcoplasmic reticulum Ca2+ content, decreased Ca2+ transient amplitude, and increased frequency of Ca2+ waves. These results are in line with a decreased threshold for diastolic Ca2+ release established by other studies. In the present study, factors that might contribute to a lower threshold for diastolic Ca2+ release were increased THR286 phosphorylation of Ca2+/calmodulin-dependent protein kinase II and increased protein phosphatase 1 abundance. In conclusion, this study demonstrates both decreased sarcoplasmic reticulum Ca2+ content and increased propensity for diastolic Ca2+ release events in ventricular cardiomyocytes from rats with heart failure after myocardial infarction, and that these phenomena are also found in rats with large myocardial infarctions without heart failure development. Importantly, beta-adrenoceptor stimulation is necessary to reveal these perturbations in Ca2+ handling after a myocardial infarction.
细胞内钙离子处理异常会导致心力衰竭时的收缩功能障碍和心律失常。在心力衰竭模型中，由于肌浆网钙离子含量减少导致钙离子瞬变幅度降低是常见现象。然而，心力衰竭模型还显示，当肌浆网钙离子含量超过一定阈值水平时，舒张期钙离子释放事件的倾向增加。这种钙离子释放事件可引发心律失常。在本研究中，我们旨在探究与假手术对照组相比，心肌梗死后六周不同心功能状态大鼠的左心室心肌细胞中是否能发现钙离子稳态改变的这两个方面。采用视频边缘检测、全细胞钙离子成像和共聚焦线扫描成像来研究心肌细胞的收缩特性、钙离子瞬变和钙离子波。在基线条件下，即无β-肾上腺素能受体刺激时，大面积心肌梗死但无心力衰竭的大鼠心肌细胞在细胞功能的这些方面与假手术动物无差异。然而，当受到β-肾上腺素能受体刺激时，非衰竭和衰竭大鼠心脏的心肌细胞均显示肌浆网钙离子含量降低、钙离子瞬变幅度降低以及钙离子波频率增加。这些结果与其他研究确定的舒张期钙离子释放阈值降低一致。在本研究中，可能导致舒张期钙离子释放阈值降低的因素是钙离子/钙调蛋白依赖性蛋白激酶II的THR286磷酸化增加和蛋白磷酸酶1丰度增加。总之，本研究表明心肌梗死后心力衰竭大鼠的心室心肌细胞中肌浆网钙离子含量降低以及舒张期钙离子释放事件的倾向增加，并且在无心力衰竭发生的大面积心肌梗死大鼠中也发现了这些现象。重要的是，β-肾上腺素能受体刺激对于揭示心肌梗死后钙离子处理的这些扰动是必要的。
