Abstract 213: Deletion of 12/15 Lipoxygenase and Fatty Acids Interaction Alters Leukocyte Kinetics Leading to Improved Healing Following Myocardial Infarction
The 12/15 lipoxygenase (LOX) enzyme catalyzes oxygenation of fatty acids to form lipid mediators leading to non-resolving inflammation. However, how 12/15LOX interacts with PUFA (polyunsaturated fatty acids) in post-myocardial infarction (MI) cardiac healing is unclear. Here we assessed the role of 12/15LOX in post-MI cardiac remodeling in a PUFA (10% w/w, 22 Kcal) enriched environment. C57BL/6J wild-type (WT) and 12/15LOX null (12/15LOX–/–) male mice of 8-12-weeks age were fed PUFA-enriched diet for 1 month and subjected to permanent coronary artery ligation. Post-MI mice were monitored for day (d)1 or d5 along with standard diet (SD)-fed MI controls. No-MI surgery mice served as d0 controls. 12/15LOX and PUFA+12/15LOX-/- mice reduced infarcted wall thinning with decreased lung edema index at d5 post-MI (all p<0.05) despite comparable infarct area (49-52%). PUFA+WT and 12/15LOX-/- mice showed improved ejection fraction with reduced left ventricle (LV) hypertrophy index than SD+WT at d5 post-MI (p<0.05). The neutrophil density was decreased in both PUFA+WT and 12/15LOX-/- mice at d1 post-MI (P<0.05). The neutrophil clearance was rapid in 12/15LOX-/- alone and PUFA+12/15LOX-/- mice, with increases in expression of formyl peptide receptor 2 at d5 post-MI. The macrophage density was decreased in PUFA+WT and 12/15LOX-/- mice compared with their respective SD+WT control at d5 post-MI. PUFA+12/15LOX-/- mice displayed an increased expression of ccl2 (all p<0.05) in the infarct area. 12/15LOX deletion stimulated 5-LOX and heme oxygenase-1 in PUFA+12/15LOX-/- mice with increased levels of 9-and 13-hydroxyoctadecadienoic acid indicating improved resolution of inflammation at d5 post-MI. The PUFA+12/15LOX-/- mice displayed higher expression of proresolving macrophages ym-1, mrc-1 and arg-1 compared with SD+12/15LOX-/- mice at d5 post-MI (all p<0.05). Further, 12/15LOX-/- mice with or without PUFA showed reduced collagen deposition at d5 post-MI compared to SD+WT. In conclusion, deletion of 12/15LOX and short-term PUFA exposure attenuated cardiac remodeling via shortening the pro-inflammatory window, thus leading to an improved resolution of inflammation and LV function post-MI.
Author Disclosures: G.V. Halade: 2. Research Grant; Modest; R00 AT006704. V. Kain: None. K.A. Ingle: None. J.H. Kabarowski: None. S. Barnes: None. S.D. Prabhu: None.
- © 2015 by American Heart Association, Inc.