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：
8544487
负责人：
MING-HUI ZOU
金额：
$ 60.93万
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/8544487
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 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 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.

描述（由适用提供）：腹主动脉瘤（AAAS）是主动脉瘤最常见的形式，AAAS破裂每年至少导致15,000人死亡。流行的研究表明，香烟烟雾增加了AAAS 7.6倍的风险。但是，在人或动物中尚未建立香烟烟与AAA之间的结构联系。我们令人兴奋的初步数据表明，急性输注尼古丁会导致弹性蛋白降解，主动脉升高，异常表达和基质金属蛋白酶2（MMP2）的激活以及AAA在APOE敲除（APOE敲除（APOE-/ - ）小鼠中AAA的发生率增加。重要的是，我们发现AMP激活蛋白基纳（AMPK¿2）的遗传缺失显着降低了体内尼古丁或angii引起的AAA的发生率。生化和生物学分析表明，AMPK¿2对AP-2¿的磷酸化增加了其与MMP2启动子的结合，从而导致Pro-MMP2转录并转化为主动MMP2。这就是我们假设，尼古丁在香烟烟雾中激活AMPK？2通过诱导MMP2诱导AAA，从而导致随后损坏血管壁基质。我们将首先确定在体内小鼠中容器壁的破坏和动脉瘤形成是否需要AMPK？2。之后，我们将研究通过AMPK歌的尼古丁是否引起MMP2的异常表达，并且MMP2是否负责体内小鼠中血管壁基质的尼古丁增强损伤。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®2激活如何调节MMP2及其抑制剂及其抑制剂TIMP在VSMC和巨噬细胞中的表达和活性，这两种主要细胞类型在动脉症血管中。提出的关于香烟烟雾，MMP和动脉瘤发病机理之间联系的研究非常重要，因为其目标的实现将直接导致更好地理解基本的病理机制，这些病理机制有助于通过吸烟和其他风险因素进展，并且最重要的是，可以为治疗方法提供特定的可能性。