cAMP/CREB Signaling and Cardiac Function

cAMP/CREB ​​信号传导和心脏功能

• 批准号: 7217650
• 负责人: MARC R MONTMINY
• 金额: $ 47.8万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217650
• 关键词: RNA interference; adenylate cyclase; beta adrenergic receptor; biological signal transduction; cAMP response element binding protein; cardiac myocytes; chromatin immunoprecipitation; congestive heart failure; cyclic AMP; gene expression; genetically modified animals; laboratory mouse; phosphorylation; polymerase chain reaction; protein structure function; transfection /expression vector

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.

第二信使 cAMP 对维持心脏功能至关重要；细胞内环磷酸腺苷 充血性心力衰竭（CHF）时蓄积通常会减少。增加心脏细胞 cAMP 水平 通过心脏定向表达 VI 型腺苷酸环化酶 (ACvi) 可改善心脏功能和存活率 在 CHF 动物模型中。相比之下，使用 β-肾上腺素能受体 (PAR) 激动剂治疗可增加 CHF 患者的死亡率。目前正在研究解释 ACVI 有益作用的机制，但是 关于 ACvi 表达如何影响心肌细胞的转录调控知之甚少， 心脏中的其他细胞。环 AMP 已被证明可以通过 PKA 介导的细胞基因表达来刺激细胞基因表达。 转录因子 cAMP 响应元件结合蛋白 (CREB) 的磷酸化 Ser133，一种修饰，可促进共激活剂 CREB ​​结合蛋白 (CBP) 募集到 发起人。此外，cAMP 触发潜在细胞质 CREB ​​共激活因子 Transducer 进入核 调节性 CREB ​​2 (TORC2)，通过与 CREB ​​直接相互作用来增强靶基因表达 相关发起人。支持 CREB ​​在介导 cAMP 对心脏功能的影响中的作用， 在心脏中表达磷酸化缺陷的 Ser133Ala CREB ​​多肽的转基因小鼠表现出扩张 心肌病。 CREB、CBP 和 TORC2 是否以及通过什么机制介导保护作用 然而，ACvi 对心脏功能的影响尚不清楚。 该提案的总体目标是： 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. 测试CREB:TORC2通路在此过程中的作用。