Competitive displacement of phosphoinositide 3-kinase from β-adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling
Competitive displacement of phosphoinositide 3-kinase from β-adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling
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DOI：
10.1152/ajpheart.01199.2005
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发表时间：
2006-10-01
影响因子：
4.8
通讯作者：
Rockman, Howard A.
中科院分区：
文献类型：
--
作者：
Curcio, Antonio;Noma, Takahisa;Rockman, Howard A.
心肌梗死（MI）后的不良重构决定了心力衰竭的进展。衰竭心脏的特征在于β-肾上腺素能受体（β-AR）信号转导的下调，部分原因是β-AR激酶1活性增加。我们先前的研究已经表明，磷酸肌醇3-激酶（PI 3 K）的磷酸肌醇激酶（PIK）结构域的过表达通过抑制PI 3 K靶向β-AR复合物来防止β-AR下调并增强肾上腺素能激动剂反应性。为了研究防止心脏中β-AR下调是否改善MI后的心脏功能，心脏特异性过表达PIK结构域肽（TgPIK）的转基因小鼠进行左冠状动脉结扎，随后在4、8、12、16和20周进行连续超声心动图检查。尽管有相似的梗死面积，TgPIK小鼠表现出更好的收缩功能，心脏扩张较少，并改善血流动力学反应多巴酚丁胺相比，同窝对照组MI后。为了测试PI 3 K从β-AR复合物的置换，而不是PI 3 K-γ的完全丧失，对于改善心脏功能是关键的，缺乏PI 3 K-γ（PI 3 K-γ-KO）的小鼠经历MI，并且在MI后20周评估它们的心脏功能。连续超声心动图测量显示与TgPIK小鼠相比，PI 3 K-γ-KO小鼠的收缩性能严重降低。此外，仅在梗死野生型和PI 3 K-γ-KO小鼠中观察到显著的β-AR下调和脱敏，而在TgPIK小鼠中未观察到。总之，这些结果表明，心肌梗死后心室的不良重塑可以通过防止PI 3 K募集到质膜并恢复正常β-AR功能的策略来减弱。
Adverse remodeling after myocardial infarction (MI) determines the progression of heart failure. Failing hearts are characterized by downregulation of beta-adrenergic receptor (beta-AR) signaling in part because of increased beta-AR kinase 1 activity. Our previous studies have shown that overexpression of the phosphoinositide kinase (PIK) domain of phosphoinositide 3-kinase (PI3K), prevents beta-AR downregulation and enhances adrenergic agonist responsiveness by inhibiting the targeting of PI3K to the beta-AR complex. To investigate whether preventing beta-AR downregulation in the heart ameliorates cardiac function post-MI, transgenic mice with cardiac-specific overexpression of the PIK domain peptide (TgPIK) underwent left coronary artery ligation and were subsequently followed by serial echocardiography at 4, 8, 12, 16, and 20 wk. Despite having similar infarction sizes, TgPIK mice showed better systolic function, less cardiac dilatation, and improved hemodynamic response to dobutamine compared with littermate controls after MI. To test that displacement of PI3K from the beta-AR complex, but not the total loss of PI3K-gamma, is critical for amelioration of cardiac function, mice lacking the PI3K-gamma (PI3K-gamma-KO) underwent MI, and their cardiac function was assessed 20 wk post-MI. Serial echocardiographic measurements showed severe reduction in contractile performance in PI3K-gamma-KO compared with TgPIK mice. Furthermore, significant beta-AR downregulation and desensitization were only seen in infarcted wild-type and PI3K-gamma-KO mice and not in TgPIK mice. Together, these results demonstrate that adverse remodeling of the ventricle after MI can be attenuated by a strategy that prevents recruitment of PI3K to the plasma membrane and restores normal beta-AR function.