Improvement of Coronary Vascular Functions by Endothelium targeted increase in reactive oxygen species

通过内皮靶向增加活性氧来改善冠状血管功能

基本信息

批准号：
9298675
负责人：
Ruhul Abid
金额：
$ 26.65万
依托单位：
OCEAN STATE RESEARCH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2018-07-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9298675
关键词：
AKT Signaling Pathway Acute Address Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Biology Blood Vessels Blood capillaries Caliber Cardiopulmonary Cardiovascular Diseases Cardiovascular system Cause of Death Cell Proliferation Centers of Research Excellence Cessation of life Clinical Clinical Trials Coronary Coronary Arteriosclerosis Coronary Circulation Coronary Vessels Cysteine Disease Endothelial Cells Endothelium Event FOXO1A gene Foundations Generations Goals Growth Heart Heart Diseases Hypoxia In Vitro Infarction Instruction Intervention Ligation Mediating Modality Morbidity - disease rate Mus Myocardial Ischemia Myocardium Nitric Oxide Outcome Oxidants Oxidation-Reduction Oxides Pathology Pathway interactions Pharmaceutical Preparations Reactive Oxygen Species Reporting Role SRC gene Signal Transduction Sulfhydryl Compounds Testing Tetanus Helper Peptide Tetracyclines Tissues Transgenic Mice Vascular Endothelial Cell Vascular Endothelium Vascular blood supply Vasodilation Withdrawal base blood vessel development capillary density endothelial dysfunction improved in vivo in vivo Model injury and repair insight migration novel novel therapeutics response tissue culture transcription factor

项目摘要

PROJECT SUMMARY (See instructions): Ischemic heart disease (IHD) or myocardial ischemia, is a disease characterized by tissue hypoxia due to reduced blood supply to the heart muscle, usually caused by coronary artery disease. IHD is the leading cause of death and morbidity in the USA. Increase in coronary vessel diameter by vasodilatation (acute response), and increase in vessel density (delayed response) are two major defenses of myocardium from ischemic insults. While coronary vasodilatation is primarily dependent on endothelium-generated nitric oxide (NO), the increase in capillary density initially requires proliferation and migration of vascular endothelial cells (ECs). Increased levels of reactive oxygen species (ROS) are often observed in many cardiovascular diseases, including IHD, giving rise to the notion that ROS cause endothelial dysfunction. However, recent major interventional clinical trials using antioxidants (e.g. HOPE, ATBC), have largely produced negative results in reducing primary endpoints of cardiovascular death and morbidity. Reports from our lab demonstrated that reduced ROS levels inhibited signal transduction events that are essential for NO generation in the vascular endothelium and for coronary vasodilatation. Preliminary Results also showed that c-Src responds to changes in endothelial redox levels and promotes downstream Pl3K-Akt signaling, which in turn activates eNOS and inhibits the growth inhibitory transcription factor, FOXOi, in coronary vascular ECs. This application will test a novel HYPOTHESIS that conditional increase in endothelium-specific-ROS will activate c-Src-Pl3K-Akt-eN0S pathway and inhibit FOXO1, and thus, will result in coronary vasodilatation and increased vessel density in a myocardial ischemia model in vivo. Utilizing a newly developed binary transgenic mice that can induce conditional expression of Nox2 and 2-fold increase in ROS in vascular endothelium, we will determine whether EC-ROS activate c-Src-Pl3K-Akt signaling, proliferation and migration of mouse heart ECs in vitro (Aim 1); whether EC-ROS induce Pl3K-Akt-eNOS activation, NO synthesis and coronary vasodilatation (Aim 2); and whether EC-ROS increase vessel density in ischemic myocardium in an LAD ligation model in vivo (Aim 3).

项目摘要（请参阅说明）：缺血性心脏病（IHD）或心肌缺血，是一种疾病，其特征是由于冠状动脉疾病引起的血液供应减少而导致组织缺氧引起的缺氧。 IHD是美国死亡和发病率的主要原因。通过血管舒张（急性反应）增加冠状血管直径，血管密度的增加（延迟反应）是缺血性损伤的两种主要防御能力。尽管冠状动脉血管扩张主要取决于内皮产生的一氧化氮（NO），但毛细血管密度的增加最初需要血管内皮细胞（ECS）的增殖和迁移。在包括IHD在内的许多心血管疾病中，经常观察到活性氧（ROS）的水平升高，这会引起ROS引起内皮功能障碍的观念。但是，最近使用抗氧化剂（例如Hope，ATBC）进行的主要介入临床试验在很大程度上产生了负面结果，从而降低了心血管死亡和发病率的主要终点。我们实验室的报告表明，ROS水平降低抑制了信号转导事件，这对于血管内皮和冠状动脉血管舒张中的任何产生至关重要。初步结果还表明，C-SRC对内皮氧化还原水平的变化做出反应，并促进下游PL3K-AKT信号传导，进而激活eNOS并抑制冠状动脉血管EC中的生长抑制转录因子FoxOI。该应用将检验一个新的假设，即内皮特异性ROS的有条件增加将激活C-SRC-PL3K-AKT-EN0S途径并抑制FOXO1，因此，冠状动脉血管静脉化并增加了体内的血管密度，在体内肌肉症模型中。利用新发达的二元转基因小鼠可以诱导NOX2的条件表达，而血管内皮中ROS的有条件表达，我们将确定EC-ROS是否激活C-SRC-PL3K-AKT信号传导，增殖和小鼠心脏EC的迁移是否在体外（AIM 1）； EC-ROS是否诱导PL3K-AKT-ENOS激活，无合成和冠状动脉血管扩张（AIM 2）； EC-ROS是否会在体内的LAD连接模型中增加缺血性心肌的血管密度（AIM 3）。