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: 10085527
• 负责人: Ganesh V Halade
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10085527
• 关键词: Acids; Acute; Acute myocardial infarction; Advanced Development; Anti-Inflammatory Agents; Arachidonate 15-Lipoxygenase; Arachidonic Acids; Area; Attenuated; Biology; Biometry; Cardiac; Cause of Death; Chronic; Chronic Phase; Complement; Congestive Heart Failure; Data; Development; Diagnosis; EP4 receptor; Eicosanoid Receptor; Eicosanoids; Enzymes; Equilibrium; Exhibits; Fatty Acids; Fibroblasts; Generations; Geometry; Goals; Heart; Heart failure; Human; Hydroxyeicosatetraenoic Acids; ITGAM gene; Impairment; 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; PTPRC gene; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Production; Receptor Signaling; Resistance; Resolution; Role; Signal Transduction; Source; TNF gene; Testing; Therapeutic; Tissues; 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; novel; novel therapeutics; prevent; repaired; response; therapeutic evaluation

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 post-MI 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 tissue healing, and reduces LV dysfunction and mortality by promoting the formation of the resolving lipid mediators, epoxyeicosatrienoic acids, 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 myeloid-specific 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 lipid mediator generation to promote effective healing after MI, and thereby delays the progression to HF (at post-MI day 56). We will quantitate proinflammatory and proresolving mediators in the infarcted area, an approach previously technologically unfeasible, 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 generation of proresolving lipid mediators acutely and chronically after MI, and thereby facilitates LV healing and repair. Collectively, the studies proposed will define the role of 12/15LOX in the initiation, progression, and resolution of inflammation post-MI. To accomplish this, we have enlisted experts in inflammation, HF, and biostatistics to complement our expertise in lipidomics and lipid signaling. The knowledge gained will advance the development of novel therapeutic drugs to ameliorate HF.

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；因此，改善左心室（LV）功能和心肌梗死后的生存是困难的 提供治疗效果最终测试的终点。虽然多种因素会影响不良心脏 重塑和心力衰竭进展，新兴研究证实了脂质代谢异常的概念 导致慢性炎症和随后的心力衰竭。传统上，所有脂氧合酶 (LOX)- 衍生的脂质介质被认为是促炎且有害的。但急性炎症 对于心肌梗死后的愈合是必要的；因此，治疗的目标不是抑制所有炎症，而是 是为了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、改善组织愈合并减少 LV 功能障碍 通过促进溶解脂质介质环氧二十碳三烯酸的形成来降低死亡率 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：确定骨髓特异性 12/15LOX 缺乏是否会减少炎症介质 使用骨髓特异性 12/15LOX 敲除来控制 MI 后急性心力衰竭（第 1 至 5 天）的过度活跃炎症 老鼠。目标 2：测试骨髓特异性 12/15LOX 缺乏是否限制促炎并促进 促进心肌梗死后脂质介质的生成，促进有效愈合，从而延缓病情进展 至 HF（MI 后第 56 天）。我们将定量梗塞区域的促炎和促消退介质， 一种以前在技术上不可行的方法，并确定巨噬细胞的机制 特定的 12/15LOX 平衡促炎和促消退介质。目标 3：确定 MI 后是否 抑制 12/15LOX 会在 MI 后急性和慢性地增加促溶解脂质介质的产生， 从而促进左心室的愈合和修复。总的来说，拟议的研究将确定 12/15LOX 在 MI 后炎症的发生、进展和消退中的作用。为了实现这一目标，我们有 招募了炎症、心力衰竭和生物统计学方面的专家来补充我们在脂质组学和脂质方面的专业知识 发信号。所获得的知识将推动改善心力衰竭的新型治疗药物的开发。