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.

心肌梗死（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，MI后左心室（LV）功能的改善和生存率很难 提供治疗功效的最终测试的终点。虽然多种因素影响不良心脏 重塑和HF进展，新兴的研究提供了信任的概念，异常脂质代谢， 在慢性炎症和随后的HF中起重要作用。传统上，所有脂氧合酶（LOX）- 衍生的脂质介质被认为是促炎的和有害的。然而，急性炎症 是MI后愈合所必需的;因此，治疗的目标应该是 在促炎因子和抗炎因子之间达到最佳平衡。我们的数据表明 在小鼠中缺失12/15 LOX可延迟MI后HF，改善组织愈合，并减少LV功能障碍， 通过促进分解脂质介质环氧二十碳三烯酸的形成， 白细胞转化为修复性表型。这些数据表明，12/15 LOX活性是非消退性 心肌梗死后的炎症，从而对LV功能和死亡率产生负面影响。我们在小鼠中的数据， HF患者提示12/15 LOX诱导的花生四烯酸代谢的类花生酸产物，12（S）- 羟基二十碳四烯酸，延迟MI后心脏中的白细胞清除， 分辨率哪种特定的骨髓-白细胞群体有助于在移植后产生生物活性脂质介质 MI仍不清楚;我们的数据指出巨噬细胞的关键作用。因此，我们假设巨噬细胞- 12/15 LOX是心肌梗死后炎症触发和炎症消退途径的关键调节因子 愈合，这些必须平衡，以减轻HF的进展。为了验证这一假设，我们建议 三个目标。目的1：确定骨髓特异性12/15 LOX缺乏是否减少炎症介质， 使用骨髓特异性12/15 LOX基因敲除控制MI后急性HF的过度活动性炎症（第1 - 5天） 小鼠目的2：测试骨髓特异性12/15 LOX缺乏是否限制促炎性并促进 促分解脂质介质生成，以促进MI后的有效愈合，从而延迟进展 至HF（MI后第56天）。我们将定量梗死区的促炎和促消退介质， 一种以前技术上不可行的方法，并确定巨噬细胞- 特异性12/15 LOX平衡促炎和促消退介质。目的3：确定MI后是否 12/15 LOX的抑制增加了MI后急性和慢性的促分解脂质介质的产生， 从而促进LV愈合和修复。总的来说，拟议的研究将确定以下方面的作用： 12/15 LOX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，我们必须 招募炎症，HF和生物统计学专家，以补充我们在脂质组学和脂质 发信号。所获得的知识将促进改善HF的新型治疗药物的开发。