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: 10409634
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409634
• 关键词: Acids; Acute; Acute myocardial infarction; Advanced Development; Anabolism; Anti-Inflammatory Agents; 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; innovation; lipid mediator; lipid metabolism; lipidomics; macrophage; mass spectrometric imaging; 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.

总结：心肌梗死（MI）后的慢性炎症可进展为心力衰竭（HF）， 高发病率和死亡率;因此，MI后左心室（LV）功能和生存率的改善 提供治疗效果最终检验的硬终点。虽然多重因素影响不利 心脏重塑和HF进展，新兴的研究提供了这样的概念，即异常脂质 代谢对慢性炎症和随后的HF有重要作用。传统上，所有的脂氧合酶 （LOX）衍生的脂质介质已被认为是 促炎和有害的。然而，急性 炎症是早期愈合所必需的;因此，不是抑制所有炎症， 的目标 治疗应该是在促炎因子和抗炎因子之间达到最佳平衡。我们 数据表明，小鼠中12/15 LOX的缺失延迟了MI后的HF，改善了梗死愈合，并降低了LV 功能障碍和死亡率 通过促进分解脂质介质的形成， 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12/15 LOX缺乏是否减少炎症介质以控制过度活跃 使用骨髓特异性12/15 LOX敲除小鼠，在MI后急性HF中的炎症（第1至5天）。目标2：测试 骨髓特异性12/15 LOX缺乏是否限制了促炎症和促进促消退介质 在一些实施方案中，所述药物通过生物合成来促进MI后的有效愈合，从而延迟向慢性HF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， 技术上不可行的，并确定机制， 其中巨噬细胞特异性12/15 LOX平衡促炎和促消退介质。目标3：建立 心肌梗死后12/15 LOX抑制是否会急性增强促分解脂质的生物合成， 心肌梗死后慢性，从而促进LV愈合和修复。总体而言，拟议的研究将确定 12/15 LOX在肝细胞凋亡中的作用 启动、消退和进展 心肌梗死后炎症的发生。为了实现这一点， 我们已经招募了炎症、HF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。的 所获得的新知识将促进改善HF的新治疗靶点/药物的开发。

项目成果

Interaction of aging with lipoxygenase deficiency initiates hypersplenism, cardiac dysfunction, and profound leukocyte directed non-resolving inflammation.

衰老与脂氧合酶缺乏的相互作用会引发脾功能亢进、心脏功能障碍和严重的白细胞导向的非解决性炎症。

• DOI: 10.1007/s11357-021-00496-x
• 发表时间: 2022
• 期刊: GeroScience
• 影响因子: 5.6
• 作者: Kain,Vasundhara;Mat,Yusuf;Halade,GaneshV
• 通讯作者: Halade,GaneshV