Abstract 14092: Arachidonate 5 Lipoxygenase Deficiency Drives Age-Related Obesity, Macrophage Dysfunction in Cardiac Repair, and Omnipresence of Inflammation

Abstract

Introduction: Age-related inflammation is the primary hallmark of heart failure with reduced and preserved ejection fraction; however, the fundamental source of inflammation is unclear. Arachidonate 5 lipoxygenase (ALOX5) is known to direct the biosynthesis of leukotrienes and proinflammatory mediators (PIMs) that orchestrate the initiation of inflammation following myocardial infarction (MI). Hypothesis: Thus, we set out to test the role of ALOX5 to understand inflammation-resolution signaling in acute HF in aging. Methods: Male C57Bl/6J and ALOX5 -/- mice were divided into two groups: 1) young (2-4 months) and 2) aging (18 months). Mice were subjected to MI surgery that develops acute heart failure maintaining no-MI as naïve controls. Cellular and molecular mechanisms are detemined. Results: The absence of ALOX5 leads to age-related obesity with series of metabolic defects, including fatty liver. Next-gen sequencing analysis revealed that immune regulating pathways of infarcted myocardium were dysregulated in young and aging ALOX5 -/- mice compared to respective age-matched controls. In response to cardiac injury, ALOX5 -/- mice fail to initiate an inflammatory response with reduced leukotrienes B 4 and PIMs, with marked obesity-related chronic inflammation in immune defense hubs: spleen bone marrow and LV infarcted site. At the molecular level, ALOX5 deletion also reduced resolution mediators (specialized proresolving mediators; SPMs), thereby making macrophage dysfunctional with the decrease in SIRP-α. Aging superimposed on ALOX5 deficiency triggers macrophage dysfunction with the increase in proinflammatory phenotype (Ly6C hi ) and notable upregulation of CXCR4 and downregulation of resolution receptor formyl peptide receptor 2; in infarcted heart post-MI. Conclusions: Presented age-related outcome provides translational insight that ALOX5 serves as a connector for initiating PIM (turn-on) and SPMs (turn-off) essential for macrophage function and cardiac repair processes. Thus, future research is warranted to validate the role of ALOX5 in cardiometabolic defects, PIMs, and resolution mediators (SPMs) in heart failure with reduced and preserved ejection fraction.