Abstract
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 (CD11blow/F480high and CD11bhigh/F480high) with increased pro-inflammatory (CD11b+F4/80+Ly6Chi) phenotype and; 4) increased kidney injury marker NGAL with increased expression of TNF-ɑ 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.
Highlights
Heart failure (HF) is an enormous medical burden and the leading cause of mortality in aging populations [1]
Excess intake of fatty acids in both young and aging mice displayed a decrease in LOX-15 and LOX-5 compared with respective controls on standard Lab Chow (LC) diet
Excess fatty acid diet in young mice reduced LOX-12 expression compared with their aged match control on normal diet, no change was observed in LOX12 expression in aging mice fed either normal or high fatty acid diet (Figure 1C)
Summary
Heart failure (HF) is an enormous medical burden and the leading cause of mortality in aging populations [1]. Omega-6 plays an essential role in health homeostasis, we found that chronic, excessive intake of omega-6 leads to progression of non-resolving inflammation in obese aging mice, post-MI and development of bone marrow adiposity [5, 11]. The fundamental limitation of the currently published knowledge is the lack of data in regards to which specific pathway to target for enzyme(s) individually or grouped.
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