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：心肌梗死(MI)后的慢性炎症可进展为心力衰竭(HF)， 高发病率和高死亡率；因此，心肌梗死后左心功能的改善和生存 提供治疗效果终极测试的硬终端。而多重因素影响不利 心脏重塑和心力衰竭进展，新出现的研究支持了这样一个概念：异常脂质 新陈代谢对慢性炎症和随后的心衰有重要作用。传统上，所有的脂氧合酶 (LOX)衍生的脂质介体已被考虑 促炎和有害的。然而，急性 炎症是早期愈合所必需的；因此，与其抑制所有炎症， 的目标是 治疗应在促炎和消炎因子之间取得最佳平衡。我们的 数据表明，小鼠体内12/15LOX基因的缺失可以延缓心梗后心力衰竭，改善心肌梗死愈合，减少左心室。 功能障碍和死亡率 通过促进分解脂类介体的形成，极化的环孢素 白细胞向修复性表型转化。 这些数据表明，12/15LOX活动是非分辨率的基础 心肌梗死后的炎症，从而对左心功能和死亡率产生负面影响。我们在老鼠身上的数据和 心力衰竭患者建议12/15LOX诱导的花生四烯酸代谢的二十烷类产物，12(S)- 羟基二十碳四烯酸，延迟心肌梗死后白细胞清除，延缓炎症 决议。下列哪种特定的髓系白细胞对生物活性脂质介体的产生有贡献 MI仍不清楚；我们的数据表明巨噬细胞起着关键作用。因此，我们假设巨噬细胞- 产生的12/15LOX是心肌梗塞后炎症触发和消退途径的关键调节因子(S) 治疗，这些必须得到平衡，以减轻进展到心衰。为了检验这一假设，我们建议 三个目标。目的1：确定12/15LOX缺乏是否会减少炎性介质以控制过度活动 急性心梗后(第1天至第5天)急性心力衰竭的炎症，使用髓系特异的12/15LOX基因敲除小鼠。目标2：测试 髓系特异性12/15LOX缺陷是否限制促炎和促进促炎介质 促进心肌梗塞后有效愈合的生物合成，从而延缓进展为慢性心衰。 我们会 用定量和成像方法确定梗死区的促炎和促溶解介质 质谱学方法是 以前在技术上是不可行的，并通过 巨噬细胞特异性的12/15LOX平衡促炎和促溶解介质。目标3：建立 心肌梗死后抑制12/15LOX是否显著增加前分解脂的生物合成 慢性心肌梗死后，从而促进左室愈合和修复。总的来说，拟议的研究将界定 12/15LOX在细胞周期中的作用 启动、解决和进展 心肌梗塞后的炎症反应。要做到这一点， 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方面的专业知识。这个 所获得的新知识将推动开发新的治疗靶点/药物来改善心力衰竭。