Aging dysregulates D- and E-series resolvins to modulate cardiosplenic and cardiorenal network following myocardial infarction

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.

Splenic leukocytes define the resolution of inflammation in heart failure

“…Binary categorization of macrophages and neutrophils into proinflammatory M1 and N1 and proresolving M2 and N2 subsets may be oversimplified but the heterogeneity of M1/M2 or N1/N2 depends on the magnitude of LV injury and paracrine and autocrine role of SPMs (15, 23). The particular leukocyte subset depends on activated COXs and LOXs, availability of omega-3 and −6 fatty acids, and aging, which determine SPM levels in resolving and pro-inflammatory milieu in post-MI healing (24) (Figure 8G–H). Whether the SPMs expand residential macrophage population under the hemodynamic stress of myocardial injury is an area of active research (1, 10, 25).…”

“…Dietary supplementation of n-3 fatty acids rich in DHA and EPA has emerged as a preventive strategy to control inflammation in coronary heart disease (27). Imbalances in n-3 and n-6 fatty acids or excessive intake of n-6 fatty acids triggers non-resolving inflammation in aged but not in young mice post-MI (24, 25). The nexus of essential fatty acids and the biosynthesis of the resolution metabolome is an area of active research.…”

“…Infarcted LV and spleen of male C57Bl/6J mice were analyzed by flow cytometry (24). Prior to isolation, LV was perfused as described above to remove blood traces.…”

Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications

“…Additionally, a fundamental challenge to these nutritional trials is the importance of the balance that exists between oral intake and metabolism of omega-3 and omega-6 fatty acids. This delicate balance may be dysregulated in aging and obesity, leading to impaired resolution (Lopez, Kabarowski et al 2015, Halade, Kain et al 2016). In both transgenic mice and rabbits overexpressing 15-LOX, one of the key enzymes involved in the biosynthesis of SPMs, atherogenesis is significantly reduced compared to wild type controls when these animals are fed a standard chow diet (Serhan, Jain et al 2003, Merched, Ko et al 2008).…”

“…Third, biosynthesis pathways for both omega-3 and omega-6 fatty acids are complex and involve competition for enzymes to production various bioactive mediators (Levy, Clish et al 2001, Serhan 2007, Spite and Serhan 2010, Merched, Serhan et al 2011, Colas, Shinohara et al 2014, Serhan 2014, Poorani, Bhatt et al 2015) and this competition can produce isomers without proresolving actions (Dona, Fredman et al 2008, Spite, Norling et al 2009). Furthermore, similar pathways might play antagonistic roles in different cell types and/or different species (Wittwer and Hersberger 2007, Chatterjee, Komshian et al 2017) and additional factors such as aging (common in the atherosclerosis population) may alter the biosynthetic pathways (Halade, Kain et al 2016). An additional consideration is that oral administration of precursors might not produce adequate systemic or local amounts of specific bioactive mediators (Endo, Sano et al 2014), especially in the setting of a high cholesterol diet (Faggin, Puato et al 2000).…”