Lipoxygenase Signaling in Heart Failure Pathology

心肌梗塞(MI)后的慢性炎症可发展为心力衰竭(HF)。 发病率和死亡率；因此，心肌梗死后左心功能的改善和生存是困难的。 为治疗效果提供终极测试的终端。多种因素影响心脏不良反应 重塑和心力衰竭进展，新出现的研究支持了脂代谢异常的概念 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)- 衍生脂质介体一直被认为是促炎和有害的。然而，急性炎症 对于心肌梗塞后的愈合是必要的；因此，治疗的目标不是抑制所有的炎症，而是 是为了在促炎和消炎因子之间实现最佳平衡。我们的数据显示 在小鼠中，12/15LOX的缺失延迟了心梗后的心衰，改善了组织愈合，并减少了左心功能障碍和 通过促进极化的分解脂质介质--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：确定髓系特异性12/15LOX缺陷是否会降低炎症介质 使用髓系特异性12/15LOX基因敲除控制急性心梗后(第1至5天)急性心力衰竭患者的过度炎症 老鼠。目的2：测试髓系特异性12/15LOX缺陷是否限制促炎和促进炎症 促进脂质介质的产生，促进心肌梗死后的有效愈合，从而延缓进展 心衰(心梗后第56天)。我们将对梗死区的促炎和促溶解介质进行量化， 一种以前在技术上不可行的方法，并确定巨噬细胞- 特定的12/15LOX平衡促炎和促溶解介质。目标3：确定心肌梗死后 抑制12/15LOX可显著和慢性增加心肌梗死后前分解脂类介质的生成， 从而促进左心室的愈合和修复。总而言之，拟议的研究将定义 12/15LOX在心肌梗死后炎症的发生、发展和消退中的作用。要做到这一点，我们有 招募炎症、心力衰竭和生物统计学方面的专家，以补充我们在脂类组学和脂类方面的专业知识 发信号。所获得的知识将促进新型治疗药物的开发以改善心力衰竭。

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.