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: 8495393
• 负责人: Brent A French
• 金额: $ 35.69万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495393
• 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; Functional disorder; Glean; Glucose; Healthcare Systems; Heart; Heart failure; Hour; Hyperglycemia; Hyperglycemic Mice; Immune response; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Insulin; Interleukin-18; 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; 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; conditioning; cytokine; diabetic patient; experience; improved; in vivo; inhibitor/antagonist; insight; 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.

描述（由申请人提供）：在糖尿病和非糖尿病患者中，急性高血糖与较大的心肌梗塞（MI）面积和左心室功能受损独立相关。然而，急性高血糖加剧心肌损伤的机制仍不清楚，特别是在非糖尿病患者中。急性高血糖与氧化应激增加、内皮功能障碍、凝血激活和炎症增强有关。我们的初步研究表明，在非糖尿病小鼠缺血前不久诱发的急性高血糖显着增强再灌注损伤并消除缺血预适应和缺血后适应。此外，我们还发现，在再灌注前立即用特定激动剂激活腺苷 2A 受体 (A2AR) 可以消除心肌损伤的高血糖加剧，就像使用强效抗氧化剂 MPG 进行治疗一样。这些研究表明，非糖尿病患者的急性高血糖会通过中断内源性心脏保护机制、增加氧化应激和引发先天炎症反应来增加心肌梗死的严重程度。现在越来越多的证据表明，急性高血糖期间晚期糖化终产物 (AGE) 的形成通过与 AGE 受体 (RAGE) 相互作用，在加剧 MI 大小方面发挥着核心作用。我们之前的工作表明，CD4+ T 细胞上的 A2AR 在调节炎症反应中发挥着关键作用，而炎症反应对 MI 大小有重要影响，并且通过在再灌注前激活 A2AR 可以减少梗死面积。我们的初步研究表明，A2AR 的激活还可以防止心肌损伤的高血糖加剧。因此，我们假设急性高血糖通过 RAGE 刺激和增加氧化应激来增强 CD4+ T 细胞介导的先天免疫反应，从而加剧梗塞面积。为了在体内验证这一假设，我们将使用伴有急性高血糖的心肌缺血/再灌注损伤小鼠模型来实现以下具体目标：1）确定氧化应激、AGE/RAGE轴和胰岛素血糖正常化在心肌梗塞（MI）大小的高血糖恶化中的机制作用。将通过在 MI 小鼠模型中应用特定的药理学探针（有效的抗氧化剂、AGE 抑制剂、可溶性 RAGE 和胰岛素）来实现这一目标，然后评估它们对梗塞面积和再灌注后炎症反应的影响。 2) 确定携带 AGE、A2A 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塞面积的高血糖恶化。这一目标将采用一系列基因敲除小鼠（CD4-null、RAGE-null、A2AR-null 和 IL18R-null）来测试这一假设：CD4+ T 细胞上这些受体的存在在介导/调节高血糖对 MI 大小的有害影响中发挥着关键作用。 3) 应用从目标 1 和 2 中收集的机制见解来确定一种临床相关的治疗策略，能够最大限度地减少血糖正常/高血糖小鼠的 MI 大小，并使用心脏 MRI 的尖端技术确认这对 LV 结构和功能具有持久的积极影响。

项目成果

The infarct-sparing effect of IB-MECA against myocardial ischemia/reperfusion injury in mice is mediated by sequential activation of adenosine A3 and A 2A receptors.

IB-MECA 对小鼠心肌缺血/再灌注损伤的梗塞保留作用是通过腺苷 A3 和 A 2A 受体的连续激活介导的。

• DOI: 10.1007/s00395-015-0473-x
• 发表时间: 2015
• 期刊: Basic research in cardiology
• 影响因子: 9.5
• 作者: Tian,Yikui;Marshall,Melissa;French,BrentA;Linden,Joel;Yang,Zequan
• 通讯作者: Yang,Zequan

A practical approach to remote ischemic preconditioning and ischemic preconditioning against myocardial ischemia/reperfusion injury.

• DOI: 10.14440/jbm.2016.149
• 发表时间: 2016-01-01
• 期刊: Journal of biological methods
• 作者: Totzeck, Matthias;Hendgen-Cotta, Ulrike B;Rassaf, Tienush
• 通讯作者: Rassaf, Tienush

Acute hyperglycemia abolishes ischemic preconditioning by inhibiting Akt phosphorylation: normalizing blood glucose before ischemia restores ischemic preconditioning.

• DOI: 10.1155/2013/329183
• 发表时间: 2013
• 期刊: Oxidative medicine and cellular longevity
• 作者: Yang Z;Tian Y;Liu Y;Hennessy S;Kron IL;French BA
• 通讯作者: French BA

Adenosine 2B Receptor Activation Reduces Myocardial Reperfusion Injury by Promoting Anti-Inflammatory Macrophages Differentiation via PI3K/Akt Pathway.

腺苷 2B 受体激活通过 PI3K/Akt 途径促进抗炎巨噬细胞分化，减少心肌再灌注损伤

• DOI: 10.1155/2015/585297
• 发表时间: 2015
• 期刊: Oxidative medicine and cellular longevity
• 作者: Tian Y;Piras BA;Kron IL;French BA;Yang Z
• 通讯作者: Yang Z