Halade Ganesh V, Kain Vasundhara, Ingle Kevin A, Prabhu Sumanth D
Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama
Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama.
Am J Physiol Heart Circ Physiol. 2017 Jul 1;313(1):H89-H102. doi: 10.1152/ajpheart.00040.2017. Epub 2017 Apr 14.
The metabolic transformation of fatty acids to form oxylipids using 12/15-lipoxygenase (LOX) can promote either resolving or nonresolving inflammation. However, the mechanism of how 12/15-LOX interacts with polyunsaturated fatty acids (PUFA) in postmyocardial infarction (post-MI) healing is unclear. Here, we reported the role of 12/15-LOX in post-MI cardiac remodeling in a PUFA [10% (wt/wt), 22 kcal]-enriched environment. Wild-type (WT; C57BL/6J) and 12/15-LOX-null (12/15-LOX) male mice of 8-12 wk of age were fed a PUFA-enriched diet for 1 mo and subjected to permanent coronary artery ligation. Post-MI mice were monitored for or until along with standard diet-fed MI controls. No-MI surgery mice served as naïve controls. PUFA-fed WT and 12/15-LOX mice improved ejection fraction and reduced lung edema greater than WT mice at post-MI ( < 0.05). Post-MI, neutrophil density was decreased in PUFA-fed WT and 12/15-LOX mice at ( < 0.05). Deletion of 12/15-LOX in mice led to increased cytochrome -450-derived bioactive lipid mediator epoxyeicosatrienoic acids (EETs), i.e., 11,12-EpETrE and 14,15-EpETrE, which were further enhanced by acute PUFA intake post-MI. Macrophage density was decreased in WT + PUFA and 12/15-LOX mice compared with their respective standard diet-fed WT controls at post-MI. 12/15-LOX + PUFA mice displayed an increased expression of chemokine (C-C motif) ligand 2 and reparative macrophages markers (, , and , all < 0.05) in the infarcted area. Furthermore, 12/15-LOX mice, with or without PUFA, showed reduced collagen deposition at post-MI compared with WT mice. In conclusion, deletion of 12/15-LOX and short-term exposure of PUFA promoted leukocyte clearance, thereby limiting cardiac remodeling and promoting an effective resolution of inflammation. This study determined that ) deletion of 12/15-lipoxygenase (LOX) promotes the generation of epoxyeicosatrienoic acids, the cytochrome -450-derived metabolites in postmyocardial infarction (post-MI) healing; ) acute exposure of fatty acids to 12/15-LOX mice drives leukocyte (neutrophils and macrophages) clearance post-MI; and ) metabolic transformation of fats is the significant contributor in leukocyte clearance to drive either resolving or nonresolving inflammation post-MI.
使用12/15 - 脂氧合酶（LOX）将脂肪酸代谢转化为氧脂可促进炎症的消退或持续。然而，在心肌梗死后（post - MI）愈合过程中，12/15 - LOX如何与多不饱和脂肪酸（PUFA）相互作用的机制尚不清楚。在此，我们报道了在富含PUFA [10%（重量/重量），22千卡]的环境中12/15 - LOX在心肌梗死后心脏重塑中的作用。将8 - 12周龄的野生型（WT；C57BL/6J）和12/15 - LOX基因敲除（12/15 - LOX）雄性小鼠喂食富含PUFA的饮食1个月，然后进行永久性冠状动脉结扎。对心肌梗死后的小鼠进行监测 或直至 ，同时以标准饮食喂养的心肌梗死小鼠作为对照。未进行心肌梗死手术的小鼠作为未处理对照。在心肌梗死后 时，喂食PUFA的WT和12/15 - LOX小鼠的射血分数提高，肺水肿减轻，优于WT小鼠（<0.05）。心肌梗死后，在 时，喂食PUFA的WT和12/15 - LOX小鼠的中性粒细胞密度降低（<0.05）。小鼠中12/15 - LOX的缺失导致细胞色素 - 450衍生的生物活性脂质介质环氧二十碳三烯酸（EETs）增加，即11,12 - EpETrE和14,15 - EpETrE，在心肌梗死后急性摄入PUFA会进一步增强。与各自标准饮食喂养的WT对照相比，在心肌梗死后 时，WT + PUFA和12/15 - LOX小鼠中的巨噬细胞密度降低。12/15 - LOX + PUFA小鼠在梗死区域显示趋化因子（C - C基序）配体2和修复性巨噬细胞标志物（ 、 、 和 ，均<0.05）的表达增加。此外，与WT小鼠相比，有或没有PUFA的12/15 - LOX小鼠在心肌梗死后 时胶原沉积减少。总之，12/15 - LOX的缺失和PUFA的短期暴露促进了白细胞清除，从而限制了心脏重塑并促进了炎症的有效消退。本研究确定：）12/15 - 脂氧合酶（LOX）的缺失促进了环氧二十碳三烯酸的生成，这是心肌梗死后（post - MI）愈合过程中细胞色素 - 450衍生的代谢产物；）脂肪酸急性暴露于12/15 - LOX小鼠可驱动心肌梗死后白细胞（中性粒细胞和巨噬细胞）清除；）脂肪的代谢转化是白细胞清除的重要因素，可驱动心肌梗死后炎症的消退或持续。
