IGF-1 and Diabetic Heart

IGF-1 和糖尿病心脏

• 批准号: 6537875
• 负责人: JAN KAJSTURA
• 金额: $ 23.48万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537875
• 关键词: BCL2 gene /protein; Bax gene /protein; apoptosis; cardiac myocytes; cell death; diabetic cardiomyopathy; genetic transcription; genetically modified animals; hyperglycemia; insulinlike growth factor; laboratory mouse; necrosis; oxidative stress; p53 gene /protein; renin angiotensin system; tissue /cell culture

DESCRIPTION (Verbatim from the application): The long-term objective of this application is to demonstrate that diabetic cardiomyopathy is characterized by myocyte death in which the local renin-angiotensin system (RAS) plays a primary critical role. Hyperglycemia induced by streptozotocin administration is anticipated to activate the transcription factor p53, respectively, by glycosylation and phosphorylation of the C-terminal of this protein. Enhanced p53 function may upregulate p53-dependent genes, such as bax, angiotensinogen and AT1 receptor, leading to the synthesis and secretion of Ang II and the sustained phosphorylation of the tumor suppressor. This vicious cycle may promote the chronic generation of Aug II and an increased susceptibility of cells to die. The induction of bax and the downregulation of bcl-2 by p53 may potentiate not only apoptosis, but also myocyte necrosis, resulting in restructuring of the ventricular wall, chamber dilation and impaired cardiac hemodynainics. Importantly, Aug Il-mediated responses may involve the formation of reactive oxygen species (ROS). ROS may constitute the ultimate signal in the activation of the cell death pathways. Insulin-like growth factor-i (IGF-1) opposes the consequences of p53 by phosphorylating its N-terminal and by stimulating transcription of mdm2 that may lead to the interaction of Mdzn2 and p53 proteins. Mdm2-p53 complexes attenuate p53 function, Ang II concentration, ROS generation, increase in Bax, decrease in Bcl-2 and, ultimately, cell death and ventricular remodeling. These hypotheses will be tested by performing studies in normal mice and transgenic mice overexpressing IGF-1 following the imposition of diabetes. In vivo studies will be complemented with in vitro experiments utilizing myocyte cultures infected with adenoviral vectors overexpressing human mutated p53 or human wild-type p53. These cells will be exposed to high concentration of glucose to establish a cause and effect relationship between triggers of cell death, i.e., glucose and Aug II, and factors preventing, i.e., mutated p53, and promoting, i.e., wild type p53, cell death mechanisms. These multiple analyses should allow to establish whether the myocyte RAS is fundamentally implicated in the development and progression of diabetic cardiomyopathy.

描述（申请中的逐字记录）：此项目的长期目标 应用是为了证明糖尿病心肌病的特征是 局部肾素-血管紧张素系统（RAS）在心肌细胞死亡中起主要作用 关键作用。链脲佐菌素引起的高血糖是 预期分别通过以下方式激活转录因子 p53 该蛋白质 C 末端的糖基化和磷酸化。增强型 p53 功能可能上调 p53 依赖性基因，例如 bax、血管紧张素原 和 AT1 受体，导致 Ang II 的合成和分泌以及 肿瘤抑制因子的持续磷酸化。这种恶性循环可能 促进 Aug II 的慢性产生和增加的易感性 细胞死亡。 p53 诱导 bax 和下调 bcl-2 可能 不仅会促进细胞凋亡，还会促进肌细胞坏死，从而导致 心室壁重建、心室扩张和心脏受损 血液动力学。重要的是，8月II介导的反应可能涉及形成 活性氧（ROS）。 ROS 可能构成最终信号 细胞死亡途径的激活。胰岛素样生长因子-i (IGF-1) 通过磷酸化其 N 末端来对抗 p53 的后果 刺激 mdm2 转录，可能导致 Mdzn2 和 p53 蛋白。 Mdm2-p53 复合物减弱 p53 功能、Ang II 浓度、 ROS 产生、Bax 增加、Bcl-2 减少，最终导致细胞死亡 和心室重构。这些假设将通过执行来检验 在正常小鼠和过度表达 IGF-1 的转基因小鼠中进行的研究 强加糖尿病。体内研究将与体外研究相补充 利用感染腺病毒载体的肌细胞培养物进行实验 过表达人类突变型 p53 或人类野生型 p53。这些细胞将是 暴露于高浓度葡萄糖以确定因果关系 细胞死亡触发因素（即葡萄糖和 Aug II）之间的关系，以及 预防（即突变型 p53）和促进（即野生型 p53）细胞的因素 死亡机制。这些多重分析应该能够确定 肌细胞 RAS 从根本上参与了肌细胞的发育和进展 糖尿病心肌病。