Remodeling of outward K+ currents in pressure-overload heart failure
Remodeling of outward K+ currents in pressure-overload heart failure
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DOI：
10.1111/j.1540-8167.2007.00864.x
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发表时间：
2007-08-01
影响因子：
2.7
通讯作者：
Hill, Joseph A.
中科院分区：
文献类型：
--
作者：
Wang, Yanggan;Cheng, Jun;Hill, Joseph A.
目的：外向钾离子电流是动作电位复极化的关键决定因素，也是许多电生理活性药物的作用部位。此外，这些电流背后的通道的表达和加工在心脏病中发生了改变。在这里，我们研究了小鼠左心室（LV）外向K+电流的天然跨壁梯度，并描绘了心力衰竭（HF）时这些电流的疾病相关重构。方法：采用胸主动脉收缩法诱导小鼠压力超负荷心力衰竭。使用全细胞膜片钳技术记录急性游离心室肌细胞的外向K+电流。结果：在左室壁观察到明确的向外K+电流密度和Kv4.2蛋白丰度梯度，心外膜下（SEP）肌细胞的电流密度和蛋白水平明显高于心内膜下（SEN）肌细胞。电流激活和失活的电压依赖性在SEP和SEN肌细胞中相似。然而，在衰竭的LV中，SEP细胞的外向K+电流密度显著降低，而SEN细胞则没有，导致原生跨壁梯度的消除。在低压失效时，K+电流激活和失活的电压依赖性没有改变。然而，电流失活（衰减）明显加速，从失活中恢复明显减慢。与此一致，Western blot分析显示，衰竭左室中KChIP2蛋白丰度降低。结论：这是首次报道hf相关的小鼠左室外向K+电流重塑。与人类相似，疾病相关的重构在小鼠心室壁发生的方式不同，导致固有复极梯度的丧失。再加上失活后恢复缓慢，这些改变可能会促进异常冲动传导，这是一种主要的促心律失常机制。
Objectives: Outward K+ currents are critical determinants of action potential repolarization and the site of action of a number of electrophysiologically active drugs. Further, expression and processing of the channels underlying these currents is altered in heart disease. Here, we investigated the native transmural gradient of outward K+ currents in murine left ventricle (LV) and delineated disease-related remodeling of these currents in heart failure (HF).Methods: Pressure-overload heart failure was induced in mice by thoracic aortic constriction. Outward K+ currents were recorded using the whole-cell patch clamp technique in acutely dissociated ventricular myocytes.Results: Unambiguous gradients of outward K+ current density and Kv4.2 protein abundance were observed across the wall of the LV, with significantly larger current density and protein levels in subepicardial (SEP) myocytes, compared with subendocardial (SEN) myocytes. Voltage dependences of current activation and inactivation were similar in SEP and SEN myocytes. In failing LV, however, outward K+ current density was significantly decreased in SEP but not in SEN cells leading to elimination of the native transmural gradient. In failing LV, the voltage dependences of K+ current activation and inactivation were not altered. However, current inactivation (decay) was significantly accelerated and recovery from inactivation was significantly slowed. Consistent with this, Western blot analysis revealed a decrease in KChIP2 protein abundance in failing LV.Conclusions: This is the first report of HF-related remodeling of outward K+ currents in murine LV. Similar to humans, disease-related remodeling occurs differentially across the murine ventricular wall, leading to loss of the native gradient of repolarization. Together with slowed recovery from inactivation, these alterations likely promote abnormal impulse conduction, a major proarrhythmic mechanism.