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

• Published in: American journal of physiology. Heart and circulatory physiology 2017-07, Vol.313 (1), p.H89-H102
• Main Authors: Halade, Ganesh V, Kain, Vasundhara, Ingle, Kevin A, Prabhu, Sumanth D
• Format: Article
• Language: English
• Subjects: Animals; Arachidonate 12-Lipoxygenase - metabolism; Arachidonate 15-Lipoxygenase - metabolism; Collagen; Coronary artery; Cytochromes; Deletion; Density; Diet; Edema; Enzyme Activation; Fatty acids; Fatty Acids - metabolism; Healing; Heart attacks; Infarction; Kinetics; Leukocytes; Leukocytes - metabolism; Leukocytes - pathology; Lipids; Lipoxygenase; Liquid oxygen; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Protein Binding; Recovery of Function; Stroke Volume
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00040.2017

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