Inflammation and Oxidative Stress in Hyperglycemic Exacerbation of Infarct Size

梗塞面积高血糖恶化中的炎症和氧化应激

• 批准号: 7730598
• 负责人: Brent A French
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730598
• 关键词: Accounting; Acute; Acute myocardial infarction; Address; Adenosine; Admission activity; Agonist; American Heart Association; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Blood; Blood Glucose; CD4 Positive T Lymphocytes; CD4/CD8 ratio procedure; Cardiac; Cardiovascular Diseases; Cause of Death; Cessation of life; Clinical; Clinical Research; Coagulation Process; Data; Development; Diabetes Mellitus; Diabetic mouse; Figs - dietary; Functional disorder; Glean; Glucose; Healthcare Systems; Heart; Heart failure; Hour; Hyperglycemia; Hyperglycemic Mice; Immune response; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Insulin; Intervention; Ischemia; Ischemic Preconditioning; Knockout Mice; Lead; Left Ventricular Function; Left ventricular structure; Leukocytes; Magnetic Resonance Imaging; Measures; Mediating; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Natural Killer Cells; Outcome; Oxidases; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Play; Production; Publications; Purinergic P1 Receptors; Randomized Clinical Trials; Reactive Oxygen Species; Recording of previous events; Relative (related person); Reperfusion Injury; Reperfusion Therapy; Research; Research Project Grants; Role; Series; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Tissues; United States; Work; cell type; chemokine; clinically relevant; cytokine; diabetic; diabetic patient; experience; improved; in vivo; inhibitor/antagonist; insight; interleukin-18 receptor; mortality; mouse model; myocardial infarct sizing; non-diabetic; outcome forecast; prevent; public health relevance; receptor; receptor for advanced glycation endproducts; reconstitution; research study; treatment strategy

DESCRIPTION (provided by applicant): Acute hyperglycemia is independently associated with larger myocardial infarct (MI) size and impaired LV function in both diabetic and non-diabetic patients. However, the mechanisms underlying the exacerbation of myocardial injury by acute hyperglycemia remain unclear, especially in non-diabetics. Acute hyperglycemia is associated with increased oxidative stress, endothelial dysfunction, activation of coagulation and enhanced inflammation. Our preliminary studies show that acute hyperglycemia, induced shortly before ischemia in non- diabetic mice, significantly enhances reperfusion injury and abolishes both ischemic pre- and post-conditioning. Furthermore, we have shown that activation of Adenosine 2A Receptors (A2AR) with a specific agonist immediately before reperfusion abrogates the hyperglycemic exacerbation of myocardial injury, as does treatment with the potent antioxidant MPG. These studies indicate that acute hyperglycemia in non-diabetics increases the size of MI by interrupting endogenous cardioprotective mechanisms, increasing oxidative stress and provoking innate inflammatory responses. Growing evidence now indicates that the formation of advanced glycated end products (AGEs) during acute hyperglycemia plays a central role in exacerbating MI size through their interaction with the AGE receptor (RAGE). Our previous work showed that A2ARs on CD4+ T cells play a critical role in regulating the inflammatory responses that contribute importantly to MI size, and that infarct size is reduced by activating A2ARs prior to reperfusion. Our preliminary studies show that activation of A2ARs also prevents the hyperglycemic exacerbation of myocardial injury. We therefore hypothesize that acute hyperglycemia exacerbates infarct size by enhancing CD4+ T cell-mediated innate immune responses via RAGE stimulation and increasing oxidative stress. To test the hypothesis in vivo, we will use a mouse model of myocardial ischemia/reperfusion injury with acute hyperglycemia to address the following specific aims: 1) Determine the mechanistic roles of oxidative stress, the AGE/RAGE axis and glucose normalization with insulin in the hyperglycemic exacerbation of myocardial infarct (MI) size. This Aim will be pursued by applying specific pharmacologic probes (potent antioxidants, AGE inhibitors, soluble RAGE and insulin) in the murine model of MI, then assessing their impact on infarct size and post-reperfusion inflammatory responses. 2) Determine the identity of the cell types carrying the AGE, A2A and IL-18 receptors that mediate and regulate the hyperglycemic exacerbation of infarct size in vivo. This aim will employ an array of knockout mice (CD4- null, RAGE-null, A2AR-null & IL18R-null) to test the hypothesis that the presence of each of these receptors on CD4+ T cells plays a critical role in mediating/regulating the deleterious effects of hyperglycemia on MI size. 3) Apply the mechanistic insights gleaned from Aims 1 & 2 to identify a clinically-relevant treatment strategy capable of minimizing MI size in euglycemic/hyperglycemic mice and confirm that this has an enduring, positive impact on LV structure and function using cutting-edge techniques in cardiac MRI. PUBLIC HEALTH RELEVANCE: Ischemic heart disease remains the single leading cause of death in the United States, accounting for fully one out of every five deaths. Myocardial infarction (heart attack) and heart failure resulting from heart attack account for the vast majority of the death and illness associated with ischemic heart disease. Some people have high blood sugar (hyperglycemia) when they experience a heart attack, even if they have no prior history of high blood sugar. These patients die from their heart attack much more often than patients without high blood sugar. This research project will increase our understanding of why high blood sugar worsens clinical outcome in patients with heart attack, and will identify the best combination of new and existing drugs to reduce the size of heart attack in patients with (and without) high blood sugar.

描述（由申请人提供）：急性高血糖症与糖尿病和非糖尿病患者的较大心肌梗死（MI）面积和LV功能受损独立相关。然而，急性高血糖加重心肌损伤的机制尚不清楚，特别是在非糖尿病患者中。急性高血糖症与氧化应激增加、内皮功能障碍、凝血激活和炎症增强相关。我们的初步研究表明，急性高血糖症，诱导缺血前不久，在非糖尿病小鼠，显着增强再灌注损伤和取消缺血预处理和后处理。此外，我们已经表明，腺苷2A受体（A2 AR）的激活与再灌注前立即用一种特定的激动剂消除心肌损伤的高血糖恶化，与治疗有效的抗氧化剂MPG。这些研究表明，非糖尿病患者的急性高血糖症通过中断内源性心脏保护机制、增加氧化应激和引发先天性炎症反应而增加MI的大小。现在越来越多的证据表明，急性高血糖期间晚期糖基化终产物（AGEs）的形成通过与AGE受体（RAGE）的相互作用在加剧MI范围方面发挥着核心作用。我们以前的工作表明，CD 4 + T细胞上的A2 AR在调节炎症反应中起着关键作用，这些炎症反应对MI大小有重要作用，并且通过在再灌注前激活A2 AR来减少梗死面积。我们的初步研究表明，A2 ARs的激活也可以防止高血糖加重心肌损伤。因此，我们假设急性高血糖症通过RAGE刺激和增加氧化应激增强CD 4 + T细胞介导的先天免疫反应，从而加剧梗死面积。为了在体内验证这一假设，我们将使用具有急性高血糖的心肌缺血/再灌注损伤的小鼠模型来解决以下具体目标：1）确定氧化应激、AGE/β轴和胰岛素葡萄糖正常化在心肌梗死（MI）大小的高血糖恶化中的机制作用。这一目标将通过在MI小鼠模型中应用特异性药理学探针（强效抗氧化剂、AGE抑制剂、可溶性β-内酰胺酶和胰岛素）来实现，然后评估其对梗死面积和再灌注后炎症反应的影响。2)确定携带AGE、A2 A和IL-18受体的细胞类型的身份，这些受体介导和调节体内梗死面积的高血糖恶化。该目的将采用一系列敲除小鼠（CD 4- null、RAGE-null、A2 AR-null和IL 18 R-null）来测试以下假设：CD 4 + T细胞上这些受体中的每一种的存在在介导/调节高血糖症对MI大小的有害作用中起关键作用。3)应用从目标1和2中收集的机制见解，确定能够最大限度地减少正常血糖/高血糖小鼠MI大小的临床相关治疗策略，并使用心脏MRI中的尖端技术确认这对LV结构和功能具有持久的积极影响。公共卫生相关性：缺血性心脏病仍然是美国唯一的主要死因，占每五例死亡中的一例。心肌梗塞（心脏病发作）和由心脏病发作引起的心力衰竭占与缺血性心脏病相关的死亡和疾病的绝大多数。有些人有高血糖（高血糖症），当他们经历心脏病发作，即使他们没有高血糖的历史。这些患者死于心脏病发作的频率远远高于没有高血糖的患者。这项研究项目将增加我们对为什么高血糖会影响心脏病发作患者的临床结果的理解，并将确定新的和现有的药物的最佳组合，以减少高血糖患者（和没有）心脏病发作的规模。