Epac mediates β-adrenergic receptor-induced cardiomyocyte hypertrophy
Epac mediates β-adrenergic receptor-induced cardiomyocyte hypertrophy
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DOI：
10.1161/circresaha.107.164947
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发表时间：
2008-04-25
影响因子：
20.1
通讯作者：
Lezoualc'h, Frank
中科院分区：
文献类型：
--
作者：
Metrich, Melanie;Lucas, Alexandre;Lezoualc'h, Frank
肾上腺素能过度激活促进心脏肥大，并可进展为心力衰竭，心力衰竭是全球死亡的主要原因。尽管cAMP是由β-肾上腺素能受体刺激产生的最知名的信号分子之一，但其在心脏肥大中的作用机制尚不完全清楚。Epac（exchange protein directly activated by cAMP）蛋白作为新型cAMP传感器的鉴定打破了围绕cAMP和蛋白激酶A的教条。然而，它们在成熟心脏中的作用和调节仍有待确定。在这里，我们表明，心脏肥大引起的胸主动脉缩窄增加Epac 1在大鼠心肌的表达。从带状动物分离的成年心室肌细胞显示出对Epac激活的过度细胞生长。在分子水平上，Epac 1的肥大作用独立于其经典效应子Rap 1，而是涉及小GTdR Ras、磷酸酶钙调磷酸酶和Ca 2 +/钙调蛋白依赖性蛋白激酶II。重要的是，我们发现，在响应β-肾上腺素能受体刺激，Epac 1激活Ras和诱导成人心肌细胞肥大cAMP依赖性，但蛋白激酶A非依赖性的方式。Epac 1的敲低强烈减少β-肾上腺素能受体诱导的肥大程序。最后，我们首次报道Epac 1主要在人类心脏中表达，与Epac 2亚型相比，在心力衰竭中表达增加。综上所述，我们的数据表明，鸟嘌呤核苷酸交换因子Epac 1有助于β-肾上腺素能受体的肥大作用，在蛋白激酶A β-独立的方式，因此，可能代表一种新的治疗靶点，用于治疗心脏疾病。
Cardiac hypertrophy is promoted by adrenergic overactivation and can progress to heart failure, a leading cause of mortality worldwide. Although cAMP is among the most well-known signaling molecules produced by beta-adrenergic receptor stimulation, its mechanism of action in cardiac hypertrophy is not fully understood. The identification of Epac ( exchange protein directly activated by cAMP) proteins as novel sensors for cAMP has broken the dogma surrounding cAMP and protein kinase A. However, their role and regulation in the mature heart remain to be defined. Here, we show that cardiac hypertrophy induced by thoracic aortic constriction increases Epac1 expression in rat myocardium. Adult ventricular myocytes isolated from banded animals display an exaggerated cellular growth in response to Epac activation. At the molecular level, Epac1 hypertrophic effects are independent of its classic effector, Rap1, but rather involve the small GTPase Ras, the phosphatase calcineurin, and Ca2+/ calmodulin-dependent protein kinase II. Importantly, we find that in response to beta-adrenergic receptor stimulation, Epac1 activates Ras and induces adult cardiomyocyte hypertrophy in a cAMP-dependent but protein kinase A-independent manner. Knockdown of Epac1 strongly reduces beta-adrenergic receptor-induced hypertrophic program. Finally, we report for the first time that Epac1 is mainly expressed in human heart as compared with Epac2 isoform and is increased in heart failure. Taken together, our data demonstrate that the guanine nucleotide exchange factor Epac1 contributes to the hypertrophic effect of beta- adrenergic receptor in a protein kinase A beta-independent fashion and may, therefore, represent a novel therapeutic target for the treatment of cardiac disorders.