IGF-1 and Diabetic Heart

IGF-1 和糖尿病心脏

• 批准号: 6638694
• 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/6638694
• 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（逐字从应用程序中）：这个的长期目标 应用是证明糖尿病心肌病的特征是 局部肾素 - 血管紧张素系统（RAS）发挥主要的心肌病毒死亡 关键作用。链蛋白酶给药诱导的高血糖IS 预计分别通过转录因子p53激活 该蛋白C末端的糖基化和磷酸化。增强 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和分泌的合成和分泌 肿瘤抑制剂的持续磷酸化。这个恶性循环可能 促进8月II的长期产生，并提高 细胞死亡。 p53的诱导Bax和Bcl-2的下调 不仅可以增强凋亡，还可以增强肌细胞坏死，导致 对心室壁的重组，腔室扩张和心脏受损 血液快速学。重要的是，8月IL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末端并通过 刺激MDM2的转录可能导致MDZN2和 p53蛋白。 MDM2-p53复合物减弱了p53功能，ANG II浓度， ROS产生，BAX增加，Bcl-2减少，最终是细胞死亡 和心室重塑。这些假设将通过执行测试 在正常小鼠和过表达IGF-1的正常小鼠和转基因小鼠中的研究 施加糖尿病。体内研究将与体外相辅相成 使用腺病毒载体感染的心肌细胞培养物的实验 过表达人类突变的p53或人类野生型P53。这些细胞将是 暴露于高浓度的葡萄糖以建立因果关系 细胞死亡触发因素之间的关系，即葡萄糖和8月II，以及 预防突变p53和促进的因素，即野生型p53，细胞 死亡机制。这些多次分析应该允许确定是否 肌细胞RA从根本上与 糖尿病心肌病。