Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman
Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman
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DOI：
10.1093/cvr/cvu182
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发表时间：
2014-10-01
影响因子：
10.8
通讯作者：
Shattock, Michael J.
中科院分区：
文献类型：
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作者：
Boguslavskyi, Andrii;Pavlovic, Davor;Shattock, Michael J.
衰竭心肌细胞内Na+升高导致收缩功能障碍、负性力-频率关系和心律失常。虽然磷脂酶原（PLM）被认为是形成信号通路和Na/K泵活性之间的联系，其调节缺陷导致细胞内Na升高的可能性尚未研究。我们的目的是检验在PLM 3SA基因敲入小鼠中预防PLM磷酸化（其中PLM已被呈现为不可磷酸化）将加剧心脏肥大和细胞Na超负荷的假设。测试这一假设应确定是否PLM磷酸化的变化只是旁观者效应或因果关系参与疾病progress.Methods和结果在野生型（WT）小鼠，主动脉收缩导致磷酸化不足的PLM没有改变Na/K泵的表达。这种PLM的磷酸化不足发生在带化后3天，并且与Na/K泵电流的进行性下降和[Na]（i）的升高相关。超声心动图、形态测定和压力-容积（PV）导管插入术分别证实了重构、扩张和收缩功能障碍。在PLM 3SA小鼠中，Na/K ATP酶的表达增加，PLM减少，使得在静止条件下的净Na/K泵电流不变（参见图1）。WT心肌细胞）;在起搏的PLM 3SA心肌细胞中，[Na+]（i）增加，正向模式Na/Ca交换减少。心脏肥大和Na/K泵抑制显着加剧带状PLM 3SA小鼠相比，带状WT。结论磷酸化PLM降低降低Na/K泵活性，加剧钠超载，收缩功能障碍，并在小鼠主动脉缩窄后的不良重塑。这为心力衰竭的治疗提供了一个新的治疗靶点。
Aims Elevation of intracellular Na in the failing myocardium contributes to contractile dysfunction, the negative force-frequency relationship, and arrhythmias. Although phospholemman (PLM) is recognized to form the link between signalling pathways and Na/K pump activity, the possibility that defects in its regulation contribute to elevation of intracellular Na has not been investigated. Our aim was to test the hypothesis that the prevention of PLM phosphorylation in a PLM3SA knock-in mouse (in which PLM has been rendered unphosphorylatable) will exacerbate cardiac hypertrophy and cellular Na overload. Testing this hypothesis should determine whether changes in PLM phosphorylation are simply bystander effects or are causally involved in disease progression.Methods and results In wild-type (WT) mice, aortic constriction resulted in hypophosphorylation of PLM with no change in Na/K pump expression. This under-phosphorylation of PLM occurred at 3 days post-banding and was associated with a progressive decline in Na/K pump current and elevation of [Na](i). Echocardiography, morphometry, and pressure-volume (PV) catheterization confirmed remodelling, dilation, and contractile dysfunction, respectively. In PLM3SA mice, expression of Na/K ATPase was increased and PLM decreased such that net Na/K pump current under quiescent conditions was unchanged (cf. WT myocytes); [Na+](i) was increased and forward-mode Na/Ca exchanger was reduced in paced PLM3SA myocytes. Cardiac hypertrophy and Na/K pump inhibition were significantly exacerbated in banded PLM3SA mice compared with banded WT.Conclusions Decreased phosphorylation of PLM reduces Na/K pump activity and exacerbates Na overload, contractile dysfunction, and adverse remodelling following aortic constriction in mice. This suggests a novel therapeutic target for the treatment of heart failure.