AMPK Endothelial Cell Dysfunction and the Metabolic Syndrome (PROGRAM PROJECT)

AMPK 内皮细胞功能障碍和代谢综合征（计划项目）

• 批准号: 8231333
• 负责人: NEIL B RUDERMAN
• 金额: $ 149.94万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231333
• 关键词: 5' -AMP-activated protein kinase; Affect; Age; Animals; Antiatherogenic; Aorta; Atherosclerosis; Biological; Blood Vessels; Capillarity; Cells; Central obesity; Cultured Cells; Diet; Disease; Dyslipidemias; Endothelial Cells; Endothelium; Enzymes; Exercise; Experimental Models; Fatty acid glycerol esters; Functional disorder; Glucose; Human; Hyperglycemia; Hypertension; Impairment; Insulin Resistance; Ischemia; Lipids; Liver; Metabolic syndrome; Mus; Muscle; Nature; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Peripheral; Post-Translational Protein Processing; Predisposition; Prevention; Program Research Project Grants; Protein Kinase; Public Health; Research; Research Personnel; Risk Factors; STK11 gene; Signal Transduction; Sucrose; TNF gene; Testing; Tissues; Transgenic Mice; Vascular Endothelial Cell; angiogenesis; atherogenesis; base; feeding; in vivo; insight; lipid metabolism; new therapeutic target; novel; premature; premature atherosclerosis; prevent; programs; response

The metabolic syndrome has been defined clinically as a disorder characterized by dyslipidemia, hypertension, central obesity, hyperglycemia and a predisposition to premature atherosclerotic cardiovascular disease and type 2 diabetes. In addition it is associated with microvascular rarefaction and impaired angiogenesis. In both humans and experimental animals the metabolic syndrome is typically accompanied and preceded by insulin resistance, lipid abnormalities and a proinflammatory state. We and others have proposed that these abnormalities could be the result of dysregulation of the fuel-sensing enzyme AMP-activated protein kinase (AMPK). This program will focus on the endothelium, which is generally believed to be the first vascular cell altered during both atherogenesis and impaired angiogenesis. Two major hypotheses will be tested: 1) that the vascular abnormalities associated with the metabolic syndrome are caused in part by dysregulation of AMPK (decreased basal activity or impaired activation) in the endothelial cell as well as peripheral tissues and 2) that such dysregulation is the result of impairment of a SIRT1/LKB1 signaling mechanism that we have demonstrated regulates AMPK activity in various cultured cells and in the liver in vivo (See Project 1). The three projects will individually and collectively characterize the SIRT1/LKB1/AMPK mechanism in cultured vascular endothelial cells and determine the effects of its activation and inhibition on the proatherogenic effects of glucose, FFA and TNF? (Projects 1, 2) and the angiogenic response to ischemia (Project 3). We will also explore the hypothesis that oxidative stress causes post-translational modifications of SIRT1 that can be prevented by AMPK activation (Projects 2, 1). Finally, we will develop transgenic mice with an endothelial cell specific deletion of SIRT1 or LKB1 (Core B). We will then assess the effect of these deletions on muscle capillarity (Projects 3 and 1) and atherogenic changes in the aorta (Project 2) in control mice and mice fed a high-fat/high sucrose diet. In addition, we will assess the anti-atherogenic and pro-angiogenic effects of exercise in these mice (Projects 1-3). A program project grant is requested because of the interactive nature of the research and the use of experimental models that are most effectively studied by multiple investigators. The metabolic syndrome affects over 60,000,000 people in the U.S. over the age of 20 and is a major public health problem. The proposed studies should both yield novel insights into the biological bases for the premature atherosclerosis and impaired angiogenesis associated with this entity and suggest new therapeutic targets for their prevention.

代谢综合征在临床上被定义为一种疾病，其特征是血脂异常，高血压，中枢性肥胖，高血糖和过早动脉粥样硬化心血管疾病和2型糖尿病的倾向。另外，它与微血管稀疏和血管生成受损有关。在人类和实验动物中，代谢综合征通常伴随并在胰岛素抵抗，脂质异常和促炎状态之前。我们和其他人提出，这些异常可能是燃料传感酶AMP激活蛋白激酶（AMPK）失调的结果。该程序将集中于内皮，通常认为这是在动脉粥样硬化和血管生成受损的过程中改变的第一个血管细胞。将测试两个主要的假设：1）与代谢综合征相关的血管异常部分是由于内皮细胞中AMPK（基础活性下降或基础活性或激活降低）以及周围组织和2）的各种失调的结果所引起的。培养的细胞和体内肝脏中（见项目1）。这三个项目将单独和集体地表征培养的血管内皮细胞中SIRT1/LKB1/AMPK机制，并确定其激活和抑制对葡萄糖，FFA和TNF的促进作用的影响？ （项目1，2）以及对缺血的血管生成反应（项目3）。我们还将探讨以下假设：氧化应激会导致SIRT1翻译后修饰，而AMPK激活可以预防（项目2，1）。最后，我们将开发具有SIRT1或LKB1的内皮细胞特异性缺失的转基因小鼠（Core B）。然后，我们将评估这些缺失对肌肉毛细血管性（项目3和1）的影响以及主动脉（项目2）在对照小鼠和喂养高脂/高蔗糖饮食的小鼠中的动脉粥样硬化变化。此外，我们将评估运动中运动对这些小鼠的抗动脉粥样硬化和促血管生成作用（项目1-3）。由于研究的互动性质和使用最有效研究的实验模型的使用，因此要求提供计划项目赠款。代谢综合征在20岁以上的美国影响了6万多人，这是一个重大的公共卫生问题。拟议的研究既应对早产性动脉粥样硬化的生物碱产生新的见解，又应与该实体相关的血管生成受损，并提出了预防的新治疗靶标。