Division of Cardiovascular Sciences, Department of Medicine, University of South Florida.
Division of Nephrology, The University of Alabama at Birmingham, Alabama.
Theranostics. 2021 Jan 1;11(6):2742-2754. doi: 10.7150/thno.51183. eCollection 2021.
Immune responsive 12/15 lipoxygenase (12/15LOX)-orchestrate biosynthesis of essential inflammation-resolution mediators during acute inflammatory response in post-myocardial infarction (MI). Lack of 12/15LOX dampens proinflammatory mediator 12-(S)-hydroxyeicosatetraenoic acid (12-(S)-HETE), improves post-MI survival, through the biosynthesis of endogenous mediators epoxyeicosatrienoic acids (EETs; cypoxins) to resolve post-MI inflammation. However, the mechanism that amplifies cypoxins-directed cardiac repair in acute heart failure (AHF) and chronic HF (CHF) remains of interest in MI-directed renal inflammation. Therefore, we determined the role of EETs in macrophage-specific receptor activation in facilitating cardiac repair in 12/15LOX deficient mice experiencing HF. Risk-free young adult (8 -12 week-old) male C57BL/6J wild-type mice (WT; n = 43) and 12/15LOX mice (n = 31) were subjected to permanent coronary artery ligation and monitored at day (d)1, d5 (as acute HF), and d28 to d56 (8 weeks; chronic HF) post-surgery maintaining no-MI mice that served as d0 naïve controls. Left ventricle (LV) infarcted area of 12/15LOX mice displayed an increase in expression of prostanoid receptor EP4 along with monocyte chemoattractant protein-1 CCL2 in AHF and CHF. The transcriptome analysis of isolated leukocytes (macrophages/neutrophils) from infarcted LV revealed a higher expression of EP4 on reparative macrophages expressing in 12/15LOX mice. Deletion of 12/15LOX differentially modulated the miRNA levels, downregulating miR-23a-3p (20 fold; < 0.05) and upregulating miR-125a-5p (160 fold; < 0.05) in AHF which promoted polarization of the macrophages towards reparative phenotype. Furthermore, 12/15LOX deletion markedly attenuated renal inflammation with reduced levels of NGAL and KIM-1 and apoptotic markers in the kidney during CHF. In risk-free mice during physiological cardiac repair, absence of 12/15LOX promoted reparative macrophages with marked activation of EP4 signaling thereby improving post-MI survival and limiting renal inflammation in acute and advanced HF. The future studies are warranted to advance the role of EETs in macrophage receptor biology.
免疫反应性 12/15 脂氧合酶（12/15LOX）-协调心肌梗死后（MI）急性炎症反应中必需的炎症解决介质的生物合成。缺乏 12/15LOX 会抑制促炎介质 12-（S）-羟基二十碳四烯酸（12-（S）-HETE），通过生物合成内源性介质环氧二十碳三烯酸（EETs；cypoxins）来改善 MI 后炎症，从而提高 MI 后存活率。然而，在急性心力衰竭（AHF）和慢性心力衰竭（CHF）中，增强 cypoxins 靶向心脏修复的机制仍然是 MI 靶向肾炎症的研究热点。因此，我们在经历 HF 的 12/15LOX 缺陷小鼠中确定了 EETs 在巨噬细胞特异性受体激活中促进心脏修复的作用。无风险的成年雄性 C57BL/6J 野生型（WT；n = 43）和 12/15LOX 小鼠（n = 31）被置于永久性冠状动脉结扎下，并在手术后第 1 天（d1）、第 5 天（急性 HF）和第 28 天至第 56 天（慢性 HF）进行监测，维持无 MI 作为 d0 未致敏对照。12/15LOX 小鼠的左心室（LV）梗死面积显示，在 AHF 和 CHF 中，前列腺素受体 EP4 的表达增加，同时单核细胞趋化蛋白-1 CCL2 的表达增加。从梗死 LV 分离的白细胞（巨噬细胞/中性粒细胞）的转录组分析显示，在 12/15LOX 小鼠中，表达的修复性巨噬细胞上 EP4 的表达更高。12/15LOX 的缺失差异调节了 miRNA 水平，下调 miR-23a-3p（20 倍； < 0.05）并上调 miR-125a-5p（160 倍； < 0.05）在 AHF 中促进了巨噬细胞向修复表型的极化。此外，在 CHF 期间，12/15LOX 的缺失显著减轻了肾脏炎症，降低了肾脏中的 NGAL 和 KIM-1 以及凋亡标志物的水平。在生理心脏修复期间的无风险小鼠中，缺乏 12/15LOX 促进了具有显著 EP4 信号激活的修复性巨噬细胞，从而提高了 MI 后的存活率，并限制了急性和晚期 HF 中的肾脏炎症。需要进一步的研究来推进 EETs 在巨噬细胞受体生物学中的作用。
