Interaction of 12/15-lipoxygenase with fatty acids alters the leukocyte kinetics leading to improved postmyocardial infarction healing

Abstract

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 <i>day 1</i> or until <i>day 5</i> 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 <i>day 5</i> post-MI (<i>P</i> < 0.05). Post-MI, neutrophil density was decreased in PUFA-fed WT and 12/15-LOX^-/- mice at <i>day 1</i> (<i>P</i> < 0.05). Deletion of 12/15-LOX in mice led to increased cytochrome <i>P</i>-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 <i>day 5</i> post-MI. 12/15-LOX^-/- + PUFA mice displayed an increased expression of chemokine (C-C motif) ligand 2 and reparative macrophages markers (<i>Ym-1</i>, <i>Mrc-1</i>, and <i>Arg-1</i>, all <i>P</i> < 0.05) in the infarcted area. Furthermore, 12/15-LOX^-/- mice, with or without PUFA, showed reduced collagen deposition at <i>day 5</i> 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.<b>NEW & NOTEWORTHY</b> This study determined that <i>1</i>) deletion of 12/15-lipoxygenase (LOX) promotes the generation of epoxyeicosatrienoic acids, the cytochrome <i>P</i>-450-derived metabolites in postmyocardial infarction (post-MI) healing; <i>2</i>) acute exposure of fatty acids to 12/15-LOX^-/- mice drives leukocyte (neutrophils and macrophages) clearance post-MI; and <i>3</i>) metabolic transformation of fats is the significant contributor in leukocyte clearance to drive either resolving or nonresolving inflammation post-MI.