Halade Ganesh V, Kain Vasundhara, Black Laurence M, Prabhu Sumanth D, Ingle Kevin A
Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, AL 35233, USA.
Aging (Albany NY). 2016 Oct 18;8(11):2611-2634. doi: 10.18632/aging.101077.
Post-myocardial infarction (MI), overactive inflammation is the hallmark of aging, however, the mechanism is unclear. We hypothesized that excess influx of omega 6 fatty acids may impair resolution, thus impacting the cardiosplenic and cardiorenal network post-MI. Young and aging mice were fed on standard lab chow (LC) and excess fatty acid (safflower oil; SO)-enriched diet for 2 months and were then subjected to MI surgery. Despite similar infarct areas and left ventricle (LV) dysfunction post-MI, splenic mass spectrometry data revealed higher levels of arachidonic acid (AA) derived pro-inflammatory metabolites in young-SO, but minimal formation of docosanoids, D- and E- series resolvins in SO-fed aged mice. The aged mice receiving excess intake of fatty acids exhibit; 1) decreased lipoxygenases (5-,12-, and 15) in the infarcted LV; 2) lower levels of 14HDHA, RvD1, RvD5, protectin D1, 7(S)maresin1, 8-,11-,18-HEPE and RvE3 with high levels of tetranor-12-HETEs; 3) dual population of macrophages (CD11b/F480 and CD11b/F480) with increased pro-inflammatory (CD11bpF4/80Ly6C) phenotype and; 4) increased kidney injury marker NGAL with increased expression of TNF-α and IL-1β indicating MI-induced non-resolving response compared with LC-group. Thus, excess fatty acid intake magnifies the post-MI chemokine signaling and inflames the cardiosplenic and cardiorenal network towards a non-resolving microenvironment in aging.
心肌梗死后，炎症反应过度活跃是衰老的标志，但其机制尚不清楚。我们推测，ω-6脂肪酸的过量流入可能会损害炎症消退，从而影响心肌梗死后的心脾和心肾网络。将年轻和老龄小鼠喂食标准实验室饲料（LC）和富含过量脂肪酸（红花油；SO）的饲料2个月，然后进行心肌梗死手术。尽管心肌梗死后梗死面积和左心室（LV）功能障碍相似，但脾脏质谱数据显示，年轻SO组中花生四烯酸（AA）衍生的促炎代谢产物水平较高，而在喂食SO的老龄小鼠中，类二十二碳六烯酸、D-和E-系列消退素的形成极少。摄入过量脂肪酸的老龄小鼠表现为：1）梗死左心室中脂氧合酶（5-、12-和15-）减少；2）14HDHA、RvD1、RvD5、保护素D1、7(S)maresin1、8-、11-、18-HEPE和RvE3水平较低，而四去甲-12-HETEs水平较高；巨噬细胞的双群体（CD11b/F480和CD11b/F480），促炎（CD11bpF4/80Ly6C）表型增加；4）肾损伤标志物NGAL增加，并伴有TNF-α和IL-1β表达增加，表明与LC组相比，心肌梗死诱导了非消退反应。因此，过量摄入脂肪酸会放大心肌梗死后的趋化因子信号，并使心脾和心肾网络向衰老的非消退微环境炎症发展。
