Lipoxygenase Signaling in Heart Failure Pathology

心力衰竭病理学中的脂氧合酶信号转导

• 批准号: 9813328
• 负责人: Ganesh V Halade
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813328
• 关键词: Acids; Acute; Acute myocardial infarction; Advanced Development; Anabolism; Anti-inflammatory; Arachidonate 15-Lipoxygenase; Arachidonic Acids; Area; Attenuated; Biology; Biometry; Cardiac; Cause of Death; Chronic; Complement; Congestive Heart Failure; Data; Development; Diagnosis; Drug Targeting; EP4 receptor; Eicosanoid Receptor; Eicosanoids; Enzymes; Equilibrium; Exhibits; Fatty Acids; Fibroblasts; Generations; Geometry; Goals; Heart; Heart failure; Human; Hydroxyeicosatetraenoic Acids; Image; Impairment; Infarction; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-10; Kinetics; Knockout Mice; Knowledge; Left; Left Ventricular Dysfunction; Left Ventricular Function; Left Ventricular Mass; Left Ventricular Remodeling; Left ventricular structure; Leukocytes; Link; Lipids; Lipoxygenase; Lipoxygenase 1; Mass Spectrum Analysis; Measures; Mediator of activation protein; Metabolism; Methods; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myocardial Infarction; Myocardial dysfunction; Myofibroblast; Orthologous Gene; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phase; Phenotype; Population; Receptor Signaling; Resistance; Resolution; Role; Signal Transduction; Source; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; TNF gene; Testing; Therapeutic; Treatment Efficacy; Ventricular; adverse outcome; base; cardioprotection; eicosanoid metabolism; genetic approach; healing; improved; in vivo; inhibitor/antagonist; innovation; lipid mediator; lipid metabolism; macrophage; mortality; mortality risk; neutrophil; new therapeutic target; novel; prevent; quantitative imaging; repaired; response; therapeutic evaluation

Summary: Chronic inflammation following myocardial infarction (MI) can progress to heart failure (HF) with excess morbidity and mortality; therefore, improvement in left ventricular (LV) function and survival after MI are hard endpoints that provide the ultimate test of therapeutic efficacy. While multiple factors impact adverse cardiac remodeling and HF progression, emerging studies lend credence to the concept that aberrant lipid metabolism contributes importantly to chronic inflammation and subsequent HF. Traditionally, all lipoxygenase (LOX)-derived lipid mediators have been considered proinflammatory and detrimental. However, acute inflammation is necessary for early healing; therefore, rather than inhibition of all inflammation, the goal of therapy should be to achieve an optimal balance between inflammation-promoting and -resolving factors. Our data indicate that deletion of 12/15LOX in mice delays HF post-MI, improves infarct healing, and reduces LV dysfunction and mortality by promoting the formation of the resolving lipid mediators, cypoxins that polarize leukocytes to a reparative phenotype. These data suggest that 12/15LOX activity underlies non-resolving inflammation following MI, thereby negatively impacting LV function and mortality. Our data in mice and patients with HF suggest that an eicosanoid product of 12/15LOX-induced arachidonic acid metabolism, 12(S)- hydroxyeicosatetraenoic acid, delays leukocyte clearance in the post-MI heart, delaying inflammation resolution. Which specific myeloid-leukocyte population contributes to bioactive lipid mediator generation after MI remains unclear; our data point to a critical role for macrophages. Thus, we hypothesize that macrophage- produced 12/15LOX is a key regulator of both inflammation-triggering and -resolving pathway(s) after MI healing, and these must be balanced to alleviate the progression to HF. To test this hypothesis, we propose three aims. Aim 1: Determine if 12/15LOX deficiency reduces inflammatory mediators to control overactive inflammation in acute HF after MI (days 1 to 5), using a myeloid-specific 12/15LOX-knockout mice. Aim 2: Test whether myeloid-specific 12/15LOX deficiency limits proinflammatory and promotes proresolving mediators biosynthesis to promote effective healing after MI, and thereby delays the progression to chronic HF. We will determine the proinflammatory and proresolving mediators in the infarcted area using quantitative and imaging mass spectrometry approaches that were technologically unfeasible before, and determine the mechanism by which macrophage-specific 12/15LOX balances proinflammatory and proresolving mediators. Aim 3: Establish whether post-MI inhibition of 12/15LOX augments the biosynthesis of proresolving lipids acutely and chronically after MI, and thereby facilitates LV healing and repair. Collectively, the proposed studies will define the role of 12/15LOX in the initiation, resolution, and progression of inflammation post-MI. To accomplish this, we have enlisted inflammation, HF, and biostatistics experts to complement our expertise in lipid signaling. The new knowledge gained will advance the development of novel therapeutic targets/drugs to ameliorate HF.

摘要：心肌梗塞 (MI) 后的慢性炎症可进展为心力衰竭 (HF) 发病率和死亡率过高；因此，左心室 (LV) 功能的改善和 MI 后的生存率 硬终点提供治疗效果的最终测试。虽然多种因素产生不利影响 心脏重塑和心力衰竭进展，新兴研究证实了异常脂质的概念 新陈代谢对慢性炎症和随后的心力衰竭有重要影响。传统上，所有脂氧合酶 (LOX) 衍生的脂质介质已被考虑 促炎且有害。然而，急性 炎症对于早期愈合是必要的；因此，不是抑制所有炎症， 的目标 治疗应该是在炎症促进因素和消炎因素之间达到最佳平衡。我们的 数据表明，小鼠中 12/15LOX 的缺失可延迟 MI 后的 HF、改善梗死愈合并降低 LV 功能障碍和死亡率 通过促进溶解脂质介质的形成，极化的 Cypoxins 白细胞恢复表型。 这些数据表明 12/15LOX 活性是非解析的基础 心肌梗死后炎症，从而对左室功能和死亡率产生负面影响。我们在小鼠身上的数据 心力衰竭患者认为 12/15LOX 诱导的花生四烯酸代谢的类二十烷酸产物 12(S)- 羟基二十碳四烯酸，延迟 MI 后心脏中的白细胞清除，延缓炎症 解决。哪种特定的骨髓白细胞群有助于生物活性脂质介质的产生 MI 仍不清楚；我们的数据表明巨噬细胞发挥着关键作用。因此，我们假设巨噬细胞 产生的 12/15LOX 是 MI 后炎症触发和消退途径的关键调节因子 愈合，并且必须平衡这些因素以减轻心力衰竭的进展。为了检验这个假设，我们提出 三个目标。目标 1：确定 12/15LOX 缺乏是否会减少炎症介质以控制过度活跃 使用骨髓特异性 12/15LOX 敲除小鼠研究 MI 后急性心力衰竭（第 1 至 5 天）的炎症。目标 2：测试 骨髓特异性 12/15LOX 缺乏是否会限制促炎症并促进促消退介质 生物合成促进心肌梗死后有效愈合，从而延缓慢性心力衰竭的进展。 我们将 使用定量和成像确定梗死区域中的促炎和促消退介质 质谱分析方法 以前在技术上不可行，并通过以下方式确定机制 其中巨噬细胞特异性 12/15LOX 平衡促炎和促消退介质。目标 3：建立 MI 后 12/15LOX 抑制是否会急剧增强促分解脂质的生物合成 心肌梗死后长期使用，从而促进左室愈合和修复。总的来说，拟议的研究将定义 12/15LOX的作用 启动、解决和进展 MI 后的炎症。为了实现这一目标， 我们招募了炎症、心力衰竭和生物统计学专家来补充我们在脂质信号传导方面的专业知识。这 获得的新知识将促进改善心力衰竭的新治疗靶点/药物的开发。