Ca2+/calmodulin-dependent protein kinase II-dependent remodeling of Ca2+ current in pressure overload heart failure
Ca2+/calmodulin-dependent protein kinase II-dependent remodeling of Ca2+ current in pressure overload heart failure
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DOI：
10.1074/jbc.m803043200
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发表时间：
2008-09-12
影响因子：
4.8
通讯作者：
Hill, Joseph A.
中科院分区：
文献类型：
--
作者：
Wang, Yanggan;Tandan, Samvit;Hill, Joseph A.
Ca2+/钙调素依赖性蛋白激酶II （CaMKII）活性在心力衰竭（HF）中增加，心力衰竭是一种以心律失常风险显著增加为特征的综合征。活化CaMKII增加峰值l型Ca2+电流（I-Ca）和减缓ICa失活。这些事件是否有机械联系尚不清楚。用全细胞膜片钳法记录急性分离心外膜下和心内膜下小鼠左心室肌细胞的ICa。压力超负荷心力衰竭是由手术收缩胸主动脉引起的。心外膜下肌细胞的ICa密度明显大于心内膜下/肌细胞。通道成孔亚基α 1c的细胞表面表达也出现了类似的模式。在LV衰竭时，两种细胞类型的ICa密度均成比例增加，ICa失活的时间过程减慢。这种典型的变化模式表明CaMKII的作用。与此一致的是，CaMKII活性的测量显示，衰竭的左室增加了2-3倍（p < 0.05）。为了检验因果关系，我们测量了频率相关的I-Ca促进。在HF肌细胞中，camkii依赖性过程不能被诱导，这表明camkii已被最大程度激活。在衰竭肌细胞内应用活性CaMKII未引起ICa的变化。最后，通过特定肽抑制剂的内部扩散抑制CaMKII，将对照和HF肌细胞中的I-Ca密度和失活时间减少到相似的水平。钙离子密度表现出明显的跨壁梯度，这种梯度在心力衰竭时保持不变。CaMKII是一种已知的促心律失常分子，其激活是负荷性心力衰竭中ICa重塑的主要因素。
Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity is increased in heart failure (HF), a syndrome characterized by markedly increased risk of arrhythmia. Activation of CaMKII increases peak L-type Ca2+ current (I-Ca) and slows ICa inactivation. Whether these events are linked mechanistically is unknown. ICa was recorded in acutely dissociated subepicardial and subendocardial murine left ventricular (LV) myocytes using the whole cell patch clamp method. Pressure overload heart failure was induced by surgical constriction of the thoracic aorta. ICa density was significantly larger in subepicardial myocytes than in subendocardial/myocytes. Similar patterns were observed in the cell surface expression of alpha 1c, the channel pore-forming subunit. In failing LV, ICa density was increased proportionately in both cell types, and the time course of ICa inactivation was slowed. This typical pattern of changes suggested a role of CaMKII. Consistent with this, measurements of CaMKII activity revealed a 2-3-fold increase (p < 0.05) in failing LV. To test for a causal link, we measured frequency-dependent I-Ca facilitation. In HF myocytes, this CaMKII-dependent process could not be induced, suggesting already maximal activation. Internal application of active CaMKII in failing myocytes did not elicit changes in ICa. Finally, CaMKII inhibition by internal diffusion of a specific peptide inhibitor reduced I-Ca density and inactivation time course to similar levels in control and HF myocytes. ICa density manifests a significant transmural gradient, and this gradient is preserved in heart failure. Activation of CaMKII, a known pro-arrhythmic molecule, is a major contributor to ICa remodeling in load-induced heart failure.