JNK exacerbates ischemia/reperfusion injury in hyperglycemic subjects.

JNK 会加剧高血糖受试者的缺血/再灌注损伤。

• 批准号: 7851408
• 负责人: KEITH A WEBSTER
• 金额: $ 47.81万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851408
• 关键词: Acute myocardial infarction; Affect; Animal Model; Apoptosis; Apoptotic; Blood Vessels; Brain; Cardiac; Cardiac Myocytes; Caspase; Cells; Cessation of life; Drops; Echocardiography; Etiology; Evans blue stain; Fasting; Gene Expression; Glucose; Glycolysis; Heart; Hyperglycemia; Hyperglycemic Mice; Image; Imaging Techniques; Infarction; Injury; Insulin; Insulin Resistance; Ischemia; Lipids; Liver; Long-Term Effects; Magnetic Resonance Imaging; Mediating; Metabolic; Metabolic stress; Mitochondria; Modeling; Molecular; Mus; Muscle; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Obesity; Outcome; Oxidative Stress; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Predisposition; Production; Radioisotopes; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Role; Serine; Signal Transduction; Staging; Staining method; Stains; Stress; Techniques; Testing; Time; Tissues; Tracer; Wild Type Mouse; base; db/db mouse; extracellular; falls; glucose metabolism; glucose transport; in vivo; inorganic phosphate; insulin receptor substrate 1 protein; kinase inhibitor; mouse model; novel strategies; outcome forecast; programs; public health relevance; radiotracer; research study; stress-activated protein kinase 1

DESCRIPTION (provided by applicant): The mean time to reperfusion of acute myocardial infarction patients in the USA is 3-4h. The metabolic activity within the ischemic tissue over this period is a major determinant of outcome and is critically influenced by the glycemic and insulin responsive status of the subject. Inadequate glucose-stimulated insulin production and/or insulin resistance of muscle and liver cause hyperglycemia. We hypothesize that the exacerbated injury that accompanies myocardial ischemia/reperfusion in hyperglycemic subjects is at least in part the consequence of an early switch in the function of c-Jun-N-terminal kinase (JNK) from pro-survival to pro-death. We previously described an energy-dependent switch in the function of JNK in cultured cardiac myocytes. The switch occurred when cardiac myocyte ATP level fell by below 50%, a condition that sensitized myocytes to oxidative stress, and coincided with increased phosphorylation of the insulin receptor substrate-1 (IRS-1) on the inhibitory serine-307. We have now confirmed that the switch also operates in vivo when the myocardium is subjected to ischemia/reperfusion and encounters similar metabolic stress. The in vivo effect is dramatic, JNK inhibition during prolonged ischemia reduced both apoptosis and infarction by ~50%, but the same inhibition imposed on a short ischemic episode increased apoptosis >3-fold and infarct >2-fold. Because >50% of injury caused by severe ischemia/reperfusion is regulated by JNK, the switch is potentially a major contributor to the outcome of AMI. In this revised application we will determine the degree to which the etiology of hyperglycemia affects JNK metabolic switching, characterize the metabolic signals that mediate switching and determine the death/survival pathways that are affected. In Aim 1 we will determine infarction and remodeling over time by high-definition echocardiography and micro-MRI. This will be implemented in 3 models of hyperglycemia: (i) db/db mice with monogenetic susceptibility to obesity and insulin resistance. (ii) NONcNZO10 mice with polygenic susceptibility to obesity and insulin resistance. (iii) Wild type mice infused with lipid to induce insulin resistance and hyperglycemia. In Aim 2 we will use advanced imaging techniques including micro-NMR/MRI to determine the precise metabolic parameters that regulate JNK switching in normal and hyperglycemic hearts subjected to ischemia/reperfusion. In Aim 3 we will define the death pathways that are affected by the JNK switch and the long-term effects on remodeling and gene expression in the affected region of the myocardium. PUBLIC HEALTH RELEVANCE: Fasting hyperglycemia is associated with increased myocardial infarction in both animal models and patients. Fasting hyperglycemia is also associated with insulin resistance. The mechanism for the poor outcome of hyperglycemic patients to acute myocardial infarction is not known. Here we present a new hypothesis where stress kinases are activated specifically in hyperglycemic patients undergoing AMI and cause poor outcome. Experiments are proposed to test this hypothesis in mouse models. If our hypothesis is correct we will described the molecular basis for this an begin to develop new approaches for treatment.

描述（由申请人提供）：美国急性心肌梗死患者的平均再灌注时间为3- 4小时。在此期间，缺血组织内的代谢活性是结果的主要决定因素，并且受受试者的血糖和胰岛素反应状态的严重影响。葡萄糖刺激的胰岛素产生不足和/或肌肉和肝脏的胰岛素抵抗引起高血糖症。我们推测，高血糖受试者心肌缺血/再灌注损伤加重至少部分是c-Jun-N-末端激酶（JNK）功能从促生存到促死亡的早期转换的结果。我们先前描述了在培养的心肌细胞中JNK功能的能量依赖性开关。当心肌细胞ATP水平下降到50%以下时，就会发生这种转换，这种情况会使心肌细胞对氧化应激敏感，并且与抑制性丝氨酸-307上胰岛素受体底物-1（IRS-1）的磷酸化增加相一致。我们现在已经证实，当心肌受到缺血/再灌注并遇到类似的代谢应激时，该开关也在体内起作用。体内效应是显著的，在长时间缺血期间JNK抑制使细胞凋亡和梗塞减少约50%，但对短时间缺血发作施加的相同抑制使细胞凋亡增加>3倍，梗塞增加>2倍。由于>50%的严重缺血/再灌注引起的损伤是由JNK调节的，因此这种转换可能是AMI结局的主要因素。在这个修订后的申请中，我们将确定高血糖症的病因学影响JNK代谢转换的程度，表征介导转换的代谢信号，并确定受影响的死亡/存活途径。在目标1中，我们将通过高清晰度超声心动图和微型MRI确定梗死和重构随时间的变化。这将在3种高血糖症模型中实施：（i）具有肥胖症和胰岛素抗性的单基因易感性的db/db小鼠。(ii)NONCNZO 10小鼠具有肥胖和胰岛素抵抗的多基因易感性。(iii)输注脂质的野生型小鼠诱导胰岛素抵抗和高血糖症。在目标2中，我们将使用先进的成像技术，包括micro-NMR/MRI，以确定精确的代谢参数，调节JNK开关在正常和高血糖心脏缺血/再灌注。在目标3中，我们将定义受JNK开关影响的死亡途径以及对心肌受累区域重塑和基因表达的长期影响。公共卫生相关性：在动物模型和患者中，空腹高血糖与心肌梗死增加相关。空腹高血糖也与胰岛素抵抗有关。高血糖患者发生急性心肌梗死预后不良的机制尚不清楚。在这里，我们提出了一个新的假设，即应激激酶被激活，特别是在高血糖患者经历AMI和导致不良后果。提出实验来测试这一假设在小鼠模型。如果我们的假设是正确的，我们将描述这种情况的分子基础，并开始开发新的治疗方法。