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）后慢性炎症可以发展为心力衰竭（HF） 发病率和死亡率；因此，左心室（LV）功能的改善和MI后的存活率很难 提供治疗功效的最终测试的终点。而多个因素影响心脏不利 重塑和HF进展，新兴研究使脂质代谢异常的概念具有信誉 重要地对慢性炎症和随后的HF做出贡献。传统上，所有脂氧合酶（LOX） - 衍生的脂质介质被认为是促炎和有害的。但是，急性炎症 对于MI后的康复是必需的；因此，而不是抑制所有炎症，而是治疗的目标应该 要在炎症和解析因素之间取得最佳平衡。我们的数据表明 在小鼠中删除12/15lox会延迟HF后MI，改善组织愈合，并降低LV功能障碍和 通过促进分辨脂质介质的形成，环氧钠酸，以极化 白细胞对修复表型。这些数据表明，12/15LOX活性是非分辨率的基础 MI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患者表明，12/15lox诱导的花生四烯酸代谢的类类产物，12（s） - 羟基乙酸烯酸，延迟MI后心脏中的白细胞清除，延迟炎症 解决。哪种特定的髓样白细胞种群有助于生物活性脂质介质产生 Mi仍然不清楚。我们的数据表明巨噬细胞的关键作用。因此，我们假设巨噬细胞 产生的12/15lox是Mi后发炎触发和解析途径的关键调节剂 康复，必须平衡这些治疗，以减轻HF的发展。为了检验这一假设，我们提出了 三个目标。 AIM 1：确定髓样特异性12/15LOX缺乏症是否会降低炎症介质 MI后（第1至5天）控制急性HF的过度活跃炎症，使用髓样特异性12/15lox-nockout 老鼠。目标2：测试髓样特异性12/15lox缺陷是否限制并促进促进 促进脂质介质产生以促进MI后有效愈合，从而延迟了进展 到HF（在MI后第56天）。我们将在梗塞区域中定量促炎和预处理介体， 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平衡促炎和预处理介体。 AIM 3：确定MI后是否 抑制12/15lox在Mi之后急性和慢性地促进脂质介质的产生， 从而促进LV愈合和修复。共同提出的研究将定义 MI后炎症的启动，进展和分辨率12/15lox。为此，我们有 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方面的专业知识 信号。获得的知识将推动新型治疗药物的发展以改善HF。