Sub-cellular Targeting of Endothelial ROS in Myocardial Ischemia

心肌缺血中内皮活性氧的亚细胞靶向

基本信息

批准号：
9540053
负责人：
Ruhul Abid
金额：
$ 40.25万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-10 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9540053
关键词：
3-nitrotyrosine Animal Model Animals Antioxidants Biomimetics Blood Vessels Cardiac Myocytes Cardiac Surgery procedures Cardiovascular Diseases Catalytic Domain Cause of Death Cell Proliferation Cell physiology Chronic Clinical Trials Coronary Coronary Arteriosclerosis Coronary Vessels Coronary artery Data Diabetes Mellitus Down-Regulation Endothelial Cells Endothelium Enterochromaffin Cells Equilibrium Exposure to Failure Family suidae Glycosylated hemoglobin A Health Heart Heart Atrium Human Infarction Mediating Membrane Potentials Metabolic syndrome Mitochondria Molecular Morbidity - disease rate Mus Myocardial Infarction Myocardial Ischemia NADPH Oxidase Outcome Study Oxidants Patients Phenotype Production Proteins Reactive Oxygen Species Recovery Reporting SOD2 gene Signal Transduction Therapeutic Time Tissues Transgenic Organisms Vascular Endothelial Cell Vascular blood supply Vasodilation angiogenesis base blood vessel development cardiovascular disorder prevention density diabetic endothelial dysfunction fatty acid oxidation heart function human tissue improved in vivo evaluation microvascular pathology mitochondrial membrane mouse model nanoparticle novel novel strategies nucleotide metabolism overexpression subcellular targeting

项目摘要

Cardiovascular disease (CVD) is the leading cause of death in the USA. Increased levels of reactive oxygen species (ROS) are often associated with microvascular pathology in CVD, causing endothelial dysfunction and coronary artery disease and leading to myocardial ischemia and infarction (MI). However, failure of large clinical trials using antioxidants in patients with CVD, challenges the prevailing view that ROS production is damaging to the microvasculature. The overarching hypothesis put forth in this proposal is that EC NOX- derived ROS is beneficial for revascularization immediately following myocardial ischemia but becomes detrimental upon over the LT due to increase in mitochondrial ROS. The therapeutic benefit of intervening on ROS level is best realized by specific down regulation of mito-ROS in ECs that have been exposed to LT increase in NOX-ROS such as in DM. This hypothesis will be fully tested in vivo using our novel EC-specific transgenic MnSOD (MnSOD-OE) animals and supported using mitochondria-specific nitroxide and nanoparticle antioxidant in coronary vessels from CVD patients with DM undergoing cardiac surgery. Specific Aim 1: Elucidate the molecular mechanisms by which ST vs LT increase in EC-specific NOX-ROS (NOX-OE mouse model) exert differential effects on EC function and angiogenesis and the recovery of the post-infarct ischemic myocardium. We hypothesize that whereas ST NOX-ROS increase induces AMPK®eNOS and AMPK®CPT1-mediated increase in mitochondrial fatty acid oxidation and dNTP synthesis, LT increase in NOX-ROS results in nitro-tyrosine-induced inactivation of MnSOD, increase in mito- ROS, decrease in mito-membrane potential and dNTP synthesis leading to reduced EC proliferation. Specific Aim 2: Determine if EC-specific MnSOD overexpression protects against the detrimental effects of LT exposure of NOX-ROS on vessel density and cardiac functions in post-infarct ischemic myocardium. We hypothesize that SOD-OE will improve post-MI recovery of the cardiac function by reducing mito-ROS and improving dNTP synthesis/EC proliferation in LT NOX-OE animals and in animals with DM. Double transgenic NOX-OE:SOD-OE vs NOX-OE, and SOD-OE with DM will be examined for post-MI recovery. Specific Aim 3: Elucidate the effects of mitochondrial-targeted nitroxide antioxidant and SOD biomimetic nanoparticles on post-infarct vessel density and recovery of cardiac function in mice and on chronic myocardial ischemia in large animals (swine) with metabolic syndrome. Specific Aim 4: Determine the effects of mitochondrial-targeted nitroxide antioxidant and SOD biomimetic nanoparticles on angiogenic potential of human coronary vessels from patients with or without DM. Coronary vessels from atrial tissues of patients (uncontrolled DM HbA1c>8.5, controlled DM HbA1c<7, and non-DM HbA1c<5.5) undergoing cardiac surgery will be examined.

心血管疾病（CVD）是美国死亡的主要原因。活性氧的水平增加物种（ROS）通常与CVD中的微血管病理有关，导致内皮功能障碍和冠状动脉疾病，导致心肌缺血和梗死（MI）。但是，大失败在CVD患者中使用抗氧化剂的临床试验挑战了ROS产生的普遍观点损害微脉管系统。该提议中提出的总体假设是EC NOX- 衍生的ROS在心肌缺血之后立即对血运重建是有益的，但由于线粒体ROS的增加而对LT的损害。干预的治疗益处 ROS水平最好通过对LT暴露于LT的EC中的Mito-Ros的特定调节来实现 NOX-ROS（例如DM）的增加。该假设将使用我们的新型EC特异性在体内进行全面检验转基因MNSOD（MNSOD-OE）动物，并使用线粒体特异性氮氧化物和 CVD患者接受心脏手术的CVD患者的冠状动脉血管中的纳米颗粒抗氧化剂。特定目标1：阐明ST与LT增加EC特异性NOX-ROS的分子机制（NOX-OE小鼠模型）对EC功能和血管生成产生差异影响以及恢复侵入后缺血性心肌。我们假设ST NOX-ROS增加诱导 AMPK®Enosandampk®CPT1介导的线粒体脂肪酸氧化和DNTP的增加合成，NOX-ROS的LT增加导致硝基酪氨酸诱导的MNSOD失活，增加Mito- ROS，降低了Mito-Mbrane电位和DNTP合成，导致EC增殖降低。特定目标2：确定EC特异性MNSOD是否过表达是否可以防止 NOX-ROS暴露于血管密度和心脏功能上的缺血性心肌的心脏功能。我们假设SOD-OE将通过减少Mito-Ros和改善LT NOX-OE动物和DM动物中的DNTP合成/EC增殖。双转基因 NOX-OE：SOD-OE与NOX-OE，将检查带有DM的SOD-OE，以进行MI后恢复。特定目标3：阐明线粒体靶向氮氧化物抗氧化剂和SOD仿生的作用有关摄入后血管密度的纳米颗粒以及小鼠和慢性的心脏功能的恢复大型动物（猪）的心肌缺血患有代谢综合征。特定目的4：确定线粒体靶向氮氧化剂抗氧化剂和SOD仿生的影响有或没有DM患者的人类冠状血管的血管生成潜力的纳米颗粒。冠状动脉来自患者心房组织的血管（不受控制的DM HBA1C> 8.5，受控DM HbA1c <7和非DM HBA1C <5.5）将检查心脏手术。