cAMP/CREB Signaling and Cardiac Function

第二信使cAMP对维持心脏功能至关重要；细胞内cAMP 在充血性心力衰竭(CHF)中，蓄积通常会减少。心脏细胞内cAMP水平升高 通过心脏定向表达VI型腺苷环化酶(ACVI)改善心脏功能和存活 在CHF的动物模型中。相反，β-肾上腺素能受体(PAR)激动剂的治疗增加 心力衰竭患者的死亡率。现在正在研究解释ACVI有益效果的机制，但 目前尚不清楚ACVI的表达如何影响心肌细胞的转录调控和 心脏中的其他细胞。已有研究表明，环状AMP通过PKA介导的基因表达刺激细胞基因表达 转录因子cAMP反应元件结合蛋白(CREB)的磷酸化 Ser133，一种促进共激活CREB结合蛋白(CBP)募集到 推动者。此外，cAMP还可触发潜在的细胞质CREB辅活化子Transducer的核内进入 受调控的CREB 2(TORC2)，通过与CREB的直接相互作用增强靶基因的表达 相关发起人。支持CREB在介导cAMP对心功能影响中的作用， 在心脏表达磷酸化缺陷Ser133Ala CREB多肽的转基因小鼠出现扩张 心肌病。CREB、CBP和TORC2是否以及通过什么机制调节保护作用 然而，ACVI对心脏功能的影响尚不清楚。 这项提案的总体目标是： 1.检测CREB是否介导ACVI对心功能和心肌细胞的有益作用 基因表达。 2.检测CREB：TORC2通路在此过程中的作用。

The second messenger cAMP appears critical for maintenance of cardiac function; intracellular cAMP accumulation is typically reduced in congestive heart failure (CHF). Increasing cellular cAMP levels in heart by cardiac-directed expression of adenyl cyclase type VI (ACvi) improves cardiac performance and survival in animal models of CHF. In contrast, treatment with beta-adrenergic receptor (PAR) agonists increases mortality in CHF patients. Mechanisms explaining the salutary effects of ACVI are now being addressed, but little is known about how ACvi expression may influence transcriptional regulation in cardiac myocytes and other cells in the heart. Cyclic AMP has been shown to stimulate cellular gene expression via the PKA-mediated phosphorylation of the transcription factor cAMP Response Element Binding protein (CREB) at Ser133, a modification that promotes recruitment of the coactivator CREB Binding Protein (CBP) to the promoter. Additionally, cAMP triggers nuclear entry of the latent cytoplasmic CREB coactivator, Transducer of Regulated CREB 2 (TORC2), which enhances target gene expression via a direct interaction with CREB on relevant promoters. Supporting a role for CREB in mediating the effects of cAMP on cardiac function, transgenic mice expressing a phosphorylation defective Ser133Ala CREB polypeptide in heart exhibit dilated cardiomyopathy. Whether and by what mechanism CREB, CBP, and TORC2 mediate the protective effects of ACvi on cardiac function, however, is unclear. The overall goals of this Proposal are: 1. To test whether CREB mediates the salutary effects of ACVI on cardiac function and cardiac myocyte gene expression. 2. To test the role of the CREB:TORC2 pathway in this process.