Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses
Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses
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DOI：
10.1172/jci64784
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发表时间：
2014-06-01
影响因子：
15.9
通讯作者：
Ishikawa, Yoshihiro
中科院分区：
文献类型：
--
作者：
Okumura, Satoshi;Fujita, Takayuki;Ishikawa, Yoshihiro
PKA磷酸化参与心肌细胞中钙（Ca 2+）处理的多个分子，被认为是β-肾上腺素能受体介导的心肌收缩力增强的主要调节因子;然而，最近鉴定出的cAMP激活的交换蛋白（EPAC）（其独立地由cAMP激活）对这一范式提出了挑战。缺乏Epac 1的小鼠（Epac 1 KO）表现出心脏收缩力下降，受磷蛋白（PLN）在丝氨酸-16（主要PKA介导的磷酸化位点）的磷酸化减少。在Epac 1 KO小鼠中，细胞内Ca 2+储存和Ca 2+运动的幅度降低;然而，PKA表达保持不变，异丙肾上腺素激活PICA改善心肌收缩力。相反，在心肌细胞中直接激活EPAC导致PLN在丝氨酸-16处的磷酸化增加，这依赖于PLC和PKC β。重要的是，Epac 1缺失保护心脏免受各种压力，而Epac 2缺失则没有保护作用。与野生型小鼠相比，主动脉缩窄诱导Epac 1 KO小鼠类似程度的心脏肥大;然而，由于心肌细胞凋亡和纤维化减少，缺乏Epac 1可预防随后的心功能障碍。同样，Epac 1 KO动物表现出对异丙肾上腺素和衰老诱导的心肌病的抵抗力，并减弱了致瘤活性。这些数据支持Epac 1作为PKA非依赖性PLN磷酸化的重要调节剂，并表明Epac 1调节心脏对各种应激的反应。
PKA phosphorylates multiple molecules involved in calcium (Ca2+) handling in cardiac myocytes and is considered to be the predominant regulator of beta-adrenergic receptor-mediated enhancement of cardiac contractility; however, recent identification of exchange protein activated by cAMP (EPAC), which is independently activated by cAMP, has challenged this paradigm. Mice lacking Epac1 (Epac1 KO) exhibited decreased cardiac contractility with reduced phospholamban (PLN) phosphorylation at serine-16, the major PKA-mediated phosphorylation site. In Epac1 KO mice, intracellular Ca2+ storage and the magnitude of Ca2+ movement were decreased; however, PKA expression remained unchanged, and activation of PICA with isoproterenol improved cardiac contractility. In contrast, direct activation of EPAC in cardiomyocytes led to increased PLN phosphorylation at serine-16, which was dependent on PLC and PKC epsilon. Importantly, Epac1 deletion protected the heart from various stresses, while Epac2 deletion was not protective. Compared with WT mice, aortic banding induced a similar degree of cardiac hypertrophy in Epac1 KO; however, lack of Epac1 prevented subsequent cardiac dysfunction as a result of decreased cardiac myocyte apoptosis and fibrosis. Similarly, Epac1 KO animals showed resistance to isoproterenol- and aging-induced cardiomyopathy and attenuation of arrhythmogenic activity. These data support Epac1 as an important regulator of PKA-independent PLN phosphorylation and indicate that Epac1 regulates cardiac responsiveness to various stresses.