Mechanism of oxidative/nitrosative stress and inflammation-induced tissue injury

氧化/亚硝化应激与炎症引起的组织损伤的机制

基本信息

批准号：
7591945
负责人：
PAL PACHER
金额：
$ 66.84万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
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
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7591945
关键词：
Abdomen Absence of pain sensation Address Adult Respiratory Distress Syndrome Age Aging Alcohols Analgesics Animal Model Anti-Inflammatory Agents Anti-inflammatory Antiinflammatory Effect Antioxidants Apoptosis Atherosclerosis Attenuated Biological Assay Blood Vessels CNR1 gene CNR2 gene Cannabidiol Cannabinoids Cardiac Cardiac Myocytes Cardiomyopathies Cardiopulmonary Bypass Cardiotoxicity Cardiovascular Diseases Cardiovascular Models Cardiovascular Physiology Cardiovascular system Cell Death Cells Clinical Collaborations Complications of Diabetes Mellitus Condition Coronary Critical Care Detection Development Disease Disease model Disruption Dose Doxorubicin Elderly Endocannabinoids Endothelial Cells Enzymes Ethanol Event Functional disorder Future Gene Expression Glucose Goals Heart failure Heavy Drinking Hepatic Homocysteine Homocystine Hypertension Inflammation Inflammatory Inflammatory Response Injury Institutes Insulin-Dependent Diabetes Mellitus Interleukin-10 Intervention Investigation Ischemia Ischemic Stroke Kidney Diseases Lead Life Ligands Liver Mediating Mediator of activation protein Metabolic Diseases Modeling Molecular Mus Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Neoplasm Metastasis Neuropathy Nitric Oxide Nociceptors Non-Insulin-Dependent Diabetes Mellitus Operative Surgical Procedures Organ Organ Transplantation Oxidants Oxidative Stress PARP inhibition Pain Pathogenesis Pathway interactions Peripheral Peroxonitrite Pharmaceutical Preparations Phase II Clinical Trials Physiological reperfusion Play Poly(ADP-ribose) Polymerases Prevention Production Rattus Reaction Reperfusion Injury Reperfusion Therapy Reporting Research Resistance Retinal Diseases Risk Risk Factors Role Septic Shock Signal Pathway Skeletal Muscle Stress Stroke Superoxides System Therapeutic Thrombosis Tissues Vascular Endothelial Growth Factors Wine adenosine receptor activation age related alcohol effect angiogenesis body system cardiovascular injury chemotherapeutic agent clinically relevant diabetic diabetic cardiomyopathy fatty acid amide hydrolase macrophage mouse model neointima formation novel protective effect receptor repaired research study sensory neuropathy tumor

Abdomen Absence of pain sensation Address Adult Respiratory Distress Syndrome Age Aging Alcohols Analgesics Animal Model Anti-Inflammatory Agents Anti-inflammatory Antiinflammatory Effect Antioxidants Apoptosis Atherosclerosis Attenuated Biological Assay Blood Vessels CNR1 gene CNR2 gene Cannabidiol Cannabinoids Cardiac Cardiac Myocytes Cardiomyopathies Cardiopulmonary Bypass Cardiotoxicity Cardiovascular Diseases Cardiovascular Models Cardiovascular Physiology Cardiovascular system Cell Death Cells Clinical Collaborations Complications of Diabetes Mellitus Condition Coronary Critical Care Detection Development Disease Disease model Disruption Dose Doxorubicin Elderly Endocannabinoids Endothelial Cells Enzymes Ethanol Event Functional disorder Future Gene Expression Glucose Goals Heart failure Heavy Drinking Hepatic Homocysteine Homocystine Hypertension Inflammation Inflammatory Inflammatory Response Injury Institutes Insulin-Dependent Diabetes Mellitus Interleukin-10 Intervention Investigation Ischemia Ischemic Stroke Kidney Diseases Lead Life Ligands Liver Mediating Mediator of activation protein Metabolic Diseases Modeling Molecular Mus Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Neoplasm Metastasis Neuropathy Nitric Oxide Nociceptors Non-Insulin-Dependent Diabetes Mellitus Operative Surgical Procedures Organ Organ Transplantation Oxidants Oxidative Stress PARP inhibition Pain Pathogenesis Pathway interactions Peripheral Peroxonitrite Pharmaceutical Preparations Phase II Clinical Trials Physiological reperfusion Play Poly(ADP-ribose) Polymerases Prevention Production Rattus Reaction Reperfusion Injury Reperfusion Therapy Reporting Research Resistance Retinal Diseases Risk Risk Factors Role Septic Shock Signal Pathway Skeletal Muscle Stress Stroke Superoxides System Therapeutic Thrombosis Tissues Vascular Endothelial Growth Factors Wine adenosine receptor activation age related alcohol effect angiogenesis body system cardiovascular injury chemotherapeutic agent clinically relevant diabetic diabetic cardiomyopathy fatty acid amide hydrolase macrophage mouse model neointima formation novel protective effect receptor repaired research study sensory neuropathy tumor

展开

项目摘要

Oxidative-nitrosative stress and poly(ADP-ribose) polymerase in cardiovascular pathophysiology and diabetic complications: cellular and molecular mechanisms. Oxidative/nitrosative stress and consequent PARP activation is a key event in the development of endothelial and myocardial dysfunction in various models of cardiovascular injury and heart failure (ischemic, drug-induced and aging-associated). Importantly, novel drug candidates targeting this pathway entering or being evaluated in Phase II trials for a variety of critical care diseases associated with reperfusion injury and inflammation, including but not limited to ischemic stroke, acute respiratory distress syndrome, thoraco-abdominal aortic aneurism (TAAA), repair surgery and the prevention of complications associated with cardiopulmonary bypass surgery, myocardial infarction (STEMI)undergoing primary percutaneous coronary intervention (PCI). We have recently demonstrated that peroxynitrite, a highly reactive oxidant formed from the reaction of nitric oxide and superoxide anion, is a key mediator of homocysteine (a recently identified risk factor for various cardiovascular disorders)-induced cell death in cardiomyocytes. Our future studies will also explore the role of superoxide, nitric oxide and peroxynitrite and interrelated signaling pathways in heart failure-induced by widely-used chemotherapeutic drug Doxorubicin. Diabetic vascular dysfunction is a major clinical problem which can lead to retinopathy, nephropathy, neuropathy and increased risk of stroke, hypertension and myocardial infarction. In collaboration with Dr. Irina Obrosova we have demonstrated that oxidative-nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation plays a key role in the development of various diabetic complications (including neuropathies, nephropathy and retinopathy). Recently we demonstrated that this pathway is also very important in the development of diabetic sensory neuropathy and neutralization of peroxynitrite or inhibition of PARP can be of significant therapeutics benefit. Our studies have also established that PARP inhibition decreases VEGF- and FGF-induced angiogenesis which plays pivotal role in the development of various retinopathies and also involved in tumor metastasis formation. In collaboration with Dr. George Hasko we have also demonstrated that adenosine receptor activation ameliorates type 1 diabetes in mice, and that A2A receptors are crucially required for IL-10 production by macrophages. Our impeding studies will also be directed towards the role of various oxidative/nitrosative stress related pathways in the development of diabetic cardiomyopathy. There is accumulating evidence indicating that endocannabinoids and synthetic cannabinergic ligands exert potent antioxidant, cytoprotective and antiinflammatory effects. Our recent studies showed that the non-psychoactive cannabinoid cannabidiol attenuated the high glucose-induced endothelial cell activation and barrier disruption, which are crucial early event underlying the development of various diabetic complications and atherosclerosis. Our future studies will also examine the role of endocannabinoid system in the development of diabetic cardiovascular complications using mouse and rat models of type 1 diabetes. These studies will also be extended to investigate the antioxidant/anti-inflammatory effects of various cannabinergic ligands on the development of vascular balloon injury-induced neointima formation, oxidative stress and inflammation, and on cardiac and vascular dysfunction associated with advanced aging and doxorubicin-induced heart failure, conditions also known to be associated with increased oxidative/nitrosative stress and PARP activation, in relevant animal models. Role of endocannabinoid system in tissue injury and inflammation. Our current studies have been focused on the role of the endocannabinoid system (ES) in the hepatic ischemic-reperfusion injury in a mouse model. These studies have demonstrated that oxidative/nitrosative stress is involved in the activation of the ES, and the stimulation of peripheral CB2 cannabinoid receptors protected against I/R-induced tissue injury by decreasing endothelial cell activation and inflammatory response and interrelated oxidative/nitrosative stress. We have recently found that mice lacking fatty acid amide hydrolase (an important enzyme which is also involved in the endocannabinoid degradation) are more resistant to age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis. Our studies have also showed that the activation of the endocannabinoid system contributes to the cardiotoxicity of the chemotherapeutic agent doxorubicin, and the inhibition of CB1 receptors may afford significant cardioprotection. Our impending studies will also be directed towards the understanding of the mechanisms of this cardioprotective effects, and on the elucidation of the role of endocannabinoid system in various models of cardiomyopathy and heart failure. Our recent collaborative studies with Dr. Rohini Kuner have established that in various pain and tissue injury models cannabinoids mediate analgesia largely via peripheral CB1 receptors in nociceptors. Our future collaborative studies with Drs. George Kunos, Bin Gao and Byoung-Joon Song will also be directed towards the investigation of the role of oxidative/nitrosative stress and endocannabinoid system in various other models of liver and metabolic disorders. The above mentioned studies may identify new pharmacological targets in various forms of tissue injury and cardiovascular dysfunction associated with increased inflammation and oxidative stress. Role of oxidative-nitrosative stress and apoptosis in ethanol-induced tissue-damage. Moderate and heavy drinking may significantly influence cardiovascular function and aging in different ways. During the course of the last decade, several research groups have reported that, in animal models of myocardial ischemia/reperfusion ethanol and non-ethanolic components of wine may have a specific protective effect on the myocardium, independent of the classical risk factors implicated in vascular atherosclerosis and thrombosis. Apoptosis is a mechanism of cell death implicated in the pathogenesis of alcohol-induced organ damage. Experimental studies have suggested alcohol-mediated apoptosis in the cardiac muscle, and there is also evidence of skeletal muscle apoptosis in long-term high-dose alcohol consumers. Apoptosis is present to a similar degree in the heart muscle of high-dose alcohol consumers and long-standing hypertensive subjects and is related to structural damage. We have recently developed an assay allowing simultaneous quantitative detection of oxidative stress and aopotosis in virtually any live cells. Our future studies will be focused on the understanding of the mechanisms of ethanol-induced oxidative/nitrosative stress and apoptosis in the cardiovascular system and also in other organ systems. We will use clinically relevant models of aging (Fisher rats developed by National Aging Institute), type 2 diabetes and atherosclerosis to address the effects of ethanol on the course of oxidative/nitrosative stress and inflammation associated with these diseases/pathological states.

心血管病理生理学和糖尿病并发症中的氧化硝化应激和聚（ADP-核糖）聚合酶：细胞和分子机制。在各种心血管损伤和心力衰竭模型中，氧化/亚硝化应激和随之而来的PARP激活是内皮和心肌功能障碍发展的关键事件（缺血性，药物诱导和与衰老相关）。重要的是，针对该途径进入或在II期试验中进行评估的新型药物候选者针对与再灌注损伤和炎症相关的多种重症监护病，包括但不限于缺血性疾病，急性呼吸窘迫综合征，胸痛 - 腹主动脉症（TAAA），腹部疗法（TAAA），维修手术和我的病情相关的疾病。（STEMI）接受原发性经皮冠状动脉干预（PCI）。我们最近证明，过氧亚硝酸盐是一种由一氧化氮和超氧化阴离子反应形成的高反应性氧化剂，是同型半胱氨酸（最近确定的各种心血管疾病的危险因素）的关键介体，可诱导的心脏模型中诱导的细胞死亡。我们未来的研究还将探讨超氧化物，一氧化氮和过氧亚硝酸盐的作用以及广泛使用的化学治疗药物阿霉素引起的心力衰竭中相互关联的信号通路。糖尿病血管功能障碍是一个主要的临床问题，可能导致视网膜病变，肾病，神经病和中风，高血压和心肌梗塞的风险增加。与Irina Obrosova博士合作，我们证明了氧化硝化应激和聚（ADP-核糖）聚合酶（PARP）激活在各种糖尿病并发症的发展中起着关键作用（包括神经病，肾病和视网膜病）。最近，我们证明，该途径在糖尿病感官神经病的发展和过氧亚硝酸盐的中和或抑制PARP方面也非常重要。我们的研究还确定，PARP抑制降低了VEGF和FGF诱导的血管生成，该血管生成在各种视网膜病的发展中起关键作用，并且还参与了肿瘤转移的形成。与乔治·哈斯科（George Hasko）博士合作，我们还证明，腺苷受体激活可以改善小鼠中的1型糖尿病，并且巨噬细胞生产IL-10的A2A受体至关重要。我们的阻碍研究还将针对各种氧化/亚硝化应激途径在糖尿病心肌病发展中的作用。有累积的证据表明内源性大麻素和合成大麻能配体具有有效的抗氧化剂，细胞保护作用和抗炎作用。我们最近的研究表明，非精神活性大麻素大麻二酚减弱了高葡萄糖诱导的内皮细胞激活和屏障破坏，这是各种糖尿病并发症和动脉粥样硬化的发展的至关重要的早期事件。我们未来的研究还将检查内源性大麻素系统在使用1型糖尿病的小鼠和大鼠模型的糖尿病心血管并发性发展中的作用。这些研究还将扩展到研究各种大麻蛋白能配体对血管球囊损伤诱导的形成，氧化应激和炎症以及心脏和血管功能障碍的抗氧化/抗炎作用以及与先进的心脏失败相关的氧化应变，以及对心脏和毒素诱导的氧化反应相关的氧化应激和炎症，并增加了int剂量的激活。在相关的动物模型中。内源性大麻素系统在组织损伤和炎症中的作用。我们目前的研究集中于内源性大麻素系统（ES）在小鼠模型中肝缺血性灌注损伤中的作用。这些研究表明，氧化/亚硝化应激与ES的激活有关，以及通过减少内皮细胞激活和炎症反应和炎性/氧化/硝基化应激的刺激受到I/R诱导的组织损伤的刺激。我们最近发现，缺乏脂肪酸酰胺水解酶的小鼠（一种参与内源性大麻素降解的重要酶）对与年龄相关的心脏功能障碍，心肌硝化应激，炎症基因表达和凋亡更具抗性。我们的研究还表明，内源性大麻素系统的激活有助于化学治疗剂阿霉素的心脏毒性，并且CB1受体的抑制作用可能具有明显的心脏保护。我们即将进行的研究还将针对理解这种心脏保护作用的机制，以及阐明内源性大麻素系统在各种心肌病和心力衰竭模型中的作用。我们最近与Rohini Kuner博士的合作研究确定，在各种疼痛和组织损伤中，大麻素模型大麻素模型在很大程度上通过伤害感受器中的外围CB1受体介导了镇痛。我们与Drs的未来合作研究。 George Kunos，Bin Gao和Byoung-Joon Song也将针对研究氧化/硝化应激和内源性大麻素在其他各种肝脏和代谢疾病模型中的作用。上述研究可能会发现与炎症增加和氧化应激相关的各种形式的组织损伤和心血管功能障碍的新药理靶标。氧化亚硝酸应激和凋亡在乙醇诱导的组织破坏中的作用。中度和大量饮酒可能会以不同的方式显着影响心血管功能和衰老。在过去十年的过程中，几个研究小组报告说，在心肌缺血/再灌注乙醇的动物模型中，葡萄酒的非乙醇成分可能对心肌具有特定的保护作用，而与在血管性动脉粥样硬化和血栓形成中所涉及的经典危险因素无关。凋亡是与酒精诱导器官损伤的发病机理有关的细胞死亡机制。实验研究表明，酒精介导的心脏肌肉凋亡，也有证据表明长期大剂量酒精消费者的骨骼肌凋亡。大剂量饮用者和长期高血压受试者的心肌的凋亡与结构损害有关。我们最近开发了一种测定法，允许在几乎所有活细胞中同时定量检测氧化应激和动脉粥样硬化。我们未来的研究将集中在心血管系统中乙醇诱导的氧化/亚硝化应激和凋亡的机制以及其他器官系统中的理解上。我们将使用临床相关的衰老模型（由国家老化研究所开发的Fisher大鼠），2型糖尿病和动脉粥样硬化来解决乙醇对与这些疾病/病理状态相关的氧化/硝化应激和炎症的影响。