Enhanced cardiac PI3Kα signalling mitigates arrhythmogenic electrical remodelling in pathological hypertrophy and heart failure
Enhanced cardiac PI3Kα signalling mitigates arrhythmogenic electrical remodelling in pathological hypertrophy and heart failure
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DOI：
10.1093/cvr/cvr283
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发表时间：
2012-02-01
影响因子：
10.8
通讯作者：
Nerbonne, Jeanne M.
中科院分区：
文献类型：
--
作者：
Yang, Kai-Chien;Jay, Patrick Y.;Nerbonne, Jeanne M.
心肌肥厚和心力衰竭与QT间期延长和致死性室性心律失常有关，这是由K+电流密度降低和复极受损引起的。最近在生理性心脏肥大小鼠模型中的研究表明，增加的磷酸肌醇-3-激酶-α（PI 3 K α）信号转导导致K+通道的上调和心室复极的正常化。方法和结果与野生型小鼠相比，由横向主动脉缩窄（TAC）诱导的左心室（LV）肥大，在心脏特异性表达组成性活性PI 3 K α（caPI 3 K α）的小鼠中，未导致心室动作电位或QT间期延长。事实上，复极化K+电流和K+通道亚单位转录增加的CaPI 3 K α + TAC左心室肌细胞的比例TAC诱导的细胞肥大。扩张型心肌病转基因模型中的充血性心力衰竭伴有QT间期和心室动作电位延长、K+电流和K+通道转录物减少。增加PI 3 K α信号，但不是肾素-血管紧张素系统阻断，在这个模型中，也导致增加K+电流和改善心室复极。结论在病理性肥厚或心力衰竭的设置，增强PI 3 K α信号的结果在上调的K+通道亚单位，正常化的K+电流密度和保存心室功能。因此，增强PI 3 K α信号传导可能是一种有用且独特的策略，可防止与心肌病相关的室性心律失常和猝死风险增加。
Aims Cardiac hypertrophy and heart failure are associated with QT prolongation and lethal ventricular arrhythmias resulting from decreased K+ current densities and impaired repolarization. Recent studies in mouse models of physiological cardiac hypertrophy revealed that increased phosphoinositide-3-kinase-alpha (PI3K alpha) signalling results in the up-regulation of K+ channels and the normalization of ventricular repolarization. The experiments here were undertaken to test the hypothesis that increased PI3K alpha signalling will counteract the adverse electrophysiological remodelling associated with pathological hypertrophy and heart failure.Methods and results In contrast to wild-type mice, left ventricular (LV) hypertrophy, induced by transverse aortic constriction (TAC), did not result in prolongation of ventricular action potentials or QT intervals in mice with cardiac-specific expression of constitutively active PI3K alpha (caPI3K alpha). Indeed, repolarizing K+ currents and K+ channel subunit transcripts were increased in caPI3K alpha + TAC LV myocytes in proportion to the TAC-induced cellular hypertrophy. Congestive heart failure in a transgenic model of dilated cardiomyopathy model is accompanied by prolonged QT intervals and ventricular action potentials, reduced K+ currents and K+ channel transcripts. Increased PI3K alpha signalling, but not renin-angiotensin system blockade, in this model also results in increased K+ currents and improved ventricular repolarization.Conclusion In the setting of pathological hypertrophy or heart failure, enhanced PI3K alpha signalling results in the up-regulation of K+ channel subunits, normalization of K+ current densities and preserved ventricular function. Augmentation of PI3K alpha signalling, therefore, may be a useful and unique strategy to protect against the increased risk of ventricular arrhythmias and sudden death associated with cardiomyopathy.