Restoration of β-adrenergic receptor signaling and contractile function in heart failure by disruption of the βARK1/phosphoinositide 3-kinase complex
Restoration of β-adrenergic receptor signaling and contractile function in heart failure by disruption of the βARK1/phosphoinositide 3-kinase complex
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DOI：
10.1161/circulationaha.104.508796
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发表时间：
2005-05-24
期刊：
影响因子：
37.8
通讯作者：
Rockman, HA
中科院分区：
文献类型：
--
作者：
Perrino, C;Prasad, SVN;Rockman, HA
背景-心肌β-肾上腺素能受体(βARs)的脱敏和下调是由βAR激酶1(βARK1)水平的增加启动的。肌醇磷脂3-激酶(PI3K)通过磷脂酰肌醇激酶(PIK)结构域与β-ARK1相互作用，靶向激动剂刺激的β-ARs，调节细胞内吞作用。我们测试了这样的假设，即抑制受体靶向的PI3K活性将改变受体转运并改善βAR信号，最终改善衰竭心肌细胞的收缩能力。方法和结果-为了竞争性地取代PI3K和βARK1，我们产生了心脏特异的PIK结构域过表达的小鼠。野生型小鼠服用7天的异丙肾上腺素可使β受体脱敏，并使其从质膜重新分布到早期和晚期的内吞体内。相反，转基因PIK的过表达阻止了β-Ars的重新分布，使其远离质膜，并保持了它们对激动剂的反应性。我们进一步测试了PIK过表达是否可以使已经建立的βAR异常正常化，并在猪快速心室起搏导致的大型动物心力衰竭模型中改善收缩功能障碍。衰竭的猪心表现出与βARK1相关的PI3K活性增加，以及显著的脱敏和β受体重新分配到内体隔室。重要的是，腺病毒将PIK结构域基因转移到衰竭的猪心肌细胞中，导致受体定位的PI3K活性降低，并恢复到接近正常的激动剂刺激的心肌细胞收缩。结论--这些数据表明，心力衰竭状态与βARK1/PI3K复合体的不适应重新分布有关，这种重新分布可以通过靶向βARK1/PI3K复合体的策略来抵消。
Background - Desensitization and downregulation of myocardial beta-adrenergic receptors ( beta ARs) are initiated by the increase in beta AR kinase 1 (beta ARK1) levels. By interacting with beta ARK1 through the phosphoinositide kinase (PIK) domain, phosphoinositide 3- kinase ( PI3K) is targeted to agonist- stimulated beta ARs, where it regulates endocytosis. We tested the hypothesis that inhibition of receptor- targeted PI3K activity would alter receptor trafficking and ameliorate beta AR signaling, ultimately improving contractility of failing cardiomyocytes.Methods and Results - To competitively displace PI3K from beta ARK1, we generated mice with cardiac- specific overexpression of the PIK domain. Seven- day isoproterenol administration in wild- type mice induced desensitization of beta ARs and their redistribution from the plasma membrane to early and late endosomes. In contrast, transgenic PIK overexpression prevented the redistribution of beta ARs away from the plasma membrane and preserved their responsiveness to agonist. We further tested whether PIK overexpression could normalize already established beta AR abnormalities and ameliorate contractile dysfunction in a large animal model of heart failure induced by rapid ventricular pacing in pigs. Failing porcine hearts showed increased beta ARK1- associated PI3K activity and marked desensitization and redistribution of beta ARs to endosomal compartments. Importantly, adenoviral gene transfer of the PIK domain in failing pig myocytes resulted in reduced receptor- localized PI3K activity and restored to nearly normal agonist- stimulated cardiomyocyte contractility.Conclusions - These data indicate that the heart failure state is associated with a maladaptive redistribution of beta ARs away from the plasma membrane that can be counteracted through a strategy that targets the beta ARK1/ PI3K complex.