AMPK as a redox sensor and modulator

AMPK 作为氧化还原传感器和调制器

基本信息

批准号：
8321368
负责人：
MING-HUI ZOU
金额：
$ 57.38万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321368
关键词：
3-nitrotyrosine 4 hydroxynonenal 5&apos -AMP-activated protein kinase AMP-activated protein kinase kinase Abbreviations Abdominal Aortic Aneurysm Achievement Acute Aneurysm Angiotensin II Animals Antioxidants Aorta Aortic Aneurysm Aortic Rupture ApoE knockout mouse Apolipoprotein E Attenuated Binding Biochemical Biological Blood Vessels Bone Marrow Bone Marrow Transplantation Caliber Cells Cessation of life Data Development Dominant-Negative Mutation Dose Elastin Epidemiologic Studies Equilibrium Gelatinase A Genetic Genetic Transcription Goals Growth Growth and Development function Human In Vitro Incidence Infusion procedures Knock-out Lead Link Liver Malondialdehyde Matrix Metalloproteinases Medial Medical Modeling Molecular Molecular Genetics Mus Nicotine Nicotinic Receptors Nuclear Translocation Operative Surgical Procedures Oxidation-Reduction Pathogenesis Pathologic Patients Peptide Hydrolases Peroxonitrite Phosphorylation Phosphorylation Site Phosphotransferases Proteins Reaction Time Reactive Nitrogen Species Reactive Oxygen Species Regulation Risk Risk Factors Rupture Ruptured Abdominal Aortic Aneurysm STK11 gene Saline Smoke Smoking Smooth Muscle Myocytes Superoxides TFAP2A gene Testing Therapeutic Tissue Inhibitor of Metalloproteinases Transcription Factor AP-2 Alpha abdominal aorta base cell type cigarette smoking gain of function in vivo inhibitor/antagonist loss of function macrophage mortality mouse model mutant promoter protein expression receptor research study sensor

项目摘要

DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAAs) is the most common form of aortic aneurysm and ruptured AAAs cause at least 15,000 deaths each year in the US. Epidemical studies suggest that cigarette smoke increases the risk of AAAs 7.6-fold. However, a causative link between cigarette smoke and AAAs has not been established in human or animals. Our exciting preliminary data indicate that acute infusion of nicotine resulted in significantly increased elastin degradation, enlargement of the aorta, abnormal expression and activation of matrix metalloproteinase 2 (MMP2), and an increased incidence of AAA in ApoE knockout (ApoE-/-) mice. Importantly, we find that genetic deletion of AMP-activated protein kina (AMPK¿2) markedly reduces the incidence of AAA caused by nicotine or AngII in vivo. Biochemical and biological analysis reveal that phosphorylation of AP-2¿ by AMPK¿2 increases its binding to the MMP2 promoter resulting in transcription of pro-MMP2 and conversion into active MMP2. Thus, Thus, we hypothesize that the activation of AMPK¿2 by nicotine in cigarette smoke instigates AAAs by the induction of MMP2 leading to subsequent damage of the vessel wall matrix. We will first establish if AMPK¿2 is required for nicotine-instigated destruction of the vessel wall and aneurysm formation in mice in vivo. After that, we will investigate if nicotine via AMPK¿2 causes aberrant expression of MMP2 and if MMP2 is responsible for nicotine-enhanced damage of the vessel wall matrix in mice in vivo. Finally, we will elucidate molecular mechanisms by which nicotine and cigarette smoke activates AMPK and how AMPK¿2 activation regulates the expression and activity of MMP2 and their inhibitors, TIMPs, in VSMC and macrophages, two major cell types in the aneurismal vessels. Proposed studies on the link between cigarette smoke, MMPs and aneurysm pathogenesis are highly significant, as the achievement of its goals will directly lead to a better understanding of the fundamental pathologic mechanisms that contribute to the progression of aneurismal degeneration by smoking and other risk factors, and most importantly, could provide specific possibilities for therapeutic approaches. PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysm (AAAs) is the most common form of aortic aneurysm and uncontrolled growth of AAAs frequently leads to rupture resulting in approximately 80% mortality. Epidemical studies suggest that cigarette smoke increases the risk of AAAs 7.6-fold and smoking is the only modifiable factor associated with the development, expansion, and rupture of AAAs. In this application, a combination of pharmacological, molecular, and genetic means with gain-of-function and loss-of-function approaches will be used to establish a causative link between cigarette smoke and AAAs in animals in vivo. The completion of this project will increase our understanding of the fundamental pathologic mechanisms that contribute to the progression of aneurismal degeneration by smoking and other risk factors, and most importantly, could provide specific possibilities for therapeutic approaches.

描述（由申请人提供）：腹主动脉瘤 (AAA) 是最常见的主动脉瘤形式，在美国，破裂的 AAA 每年导致至少 15,000 人死亡。流行病研究表明，吸烟会使 AAA 的风险增加 7.6 倍。然而，我们令人兴奋的初步数据表明，香烟烟雾与 AAA 之间的因果关系尚未确定。重要的是，我们发现，急性输注尼古丁会导致 ApoE 敲除 (ApoE-/-) 小鼠的弹性蛋白降解显着增加、主动脉增大、基质金属蛋白酶 2 (MMP2) 异常表达和激活，以及 AAA 发生率增加。体内 AMP 激活蛋白激酶 (AMPK¿2) 的基因缺失显着降低了由尼古丁或 AngII 引起的 AAA 的发生率。 AP-2 的磷酸化通过 AMPK¿ 2 增加其与 MMP2 启动子的结合，导致 MMP2 前体转录并转化为活性 MMP2。 2 香烟烟雾中的尼古丁通过诱导 MMP2 引发 AAA，导致血管壁基质的后续损伤。我们将首先确定 AMPK 是否如此。 2 是尼古丁引起的小鼠体内血管壁破坏和动脉瘤形成所必需的。之后，我们将研究尼古丁是否通过 AMPK 发挥作用。 2 会导致 MMP2 的异常表达，以及 MMP2 是否是尼古丁增强小鼠体内血管壁基质损伤的原因。最后，我们将阐明尼古丁和香烟烟雾激活 AMPK 的分子机制以及 AMPK 的作用。 MMP2 激活调节 VSMC 和巨噬细胞（动脉瘤血管中的两种主要细胞类型）中 MMP2 及其抑制剂 TIMP 的表达和活性。关于香烟烟雾、MMP 和动脉瘤发病机制之间联系的研究非常重要，因为其目标将直接导致更好地了解吸烟和其他危险因素导致动脉瘤变性进展的基本病理机制，最重要的是，可以为以下方面提供具体的可能性：治疗方法。公众健康相关性：腹主动脉瘤 (AAA) 是主动脉瘤最常见的形式，不受控制的 AAA 生长经常导致破裂，导致约 80% 的死亡率，流行病研究表明，吸烟会使 AAA 的风险增加 7.6 倍，而吸烟。是与 AAA 的发育、扩张和破裂相关的唯一可改变的因素。在本申请中，是以下因素的组合。药理学、分子和遗传手段以及功能获得和功能丧失方法将用于在动物体内建立香烟烟雾和 AAA 之间的因果关系。该项目的完成将增加我们对基本原理的理解。吸烟和其他危险因素导致动脉瘤变性进展的病理机制，最重要的是，可以为治疗方法提供特定的可能性。