Abstract 16952: Genetic Deficiency of 12/15Lipoxygenase Activates EP4 Receptor on Proresolving Macrophages to Attenuate Renal Inflammation After Myocardial Infarction
Introduction: 12/15lipoxygenase (12/15LOX) metabolites and cyclooxygenase-2(COX-2)-derived prostaglandin E2 (PGE2) are key mediators of the inflammatory response after myocardial infarction (MI); the contribution of these mediators to cardiorenal injury in this setting is unknown.
Hypothesis: 12/15LOX deletion resolves post-MI cardiorenal inflammation during the progression of heart failure via activation of the PGE2 receptor EP4 on pro-resolving macrophages.
Methods and Results: 8-12 week-old male C57BL/6J wild-type mice (WT; n=24) and 12/15LOX–/– mice (n=26) were subjected to permanent coronary artery ligation and evaluated at 1, 5, 28, and 56 d post-surgery. No-MI surgery mice served as d0 naïve controls. Compared to WT, 12/15LOX-/- mice exhibited improved post-MI survival and less adverse remodeling with improved LV function measured by echocardiography. Compared to WT, 12/15-LOX-/- mice increased the monocyte-mediated inflammatory response by activating TREM-1 with a robust increase (2.5-fold; p<0.05) in EP4 and CCL2 (3-fold, p<0.05) expression at d1 post-MI. EP4 expression was consistently elevated until d56 post-MI in 12/15LOX-/- mice compared with WT. Immunofluorescence staining showed that EP4 is highly expressed in the LV infarct area of 12/15LOX-/- mice compared to WT at post-MI d5. The mRNA analysis of isolated leukocytes from infarcted LV at d1 and d5 post-MI revealed a higher expression of EP4 on macrophages expressing MRC-1 in 12/15LOX-/- mice. Wheat germ agglutinin staining revealed smaller cardiomyocyte area in remote zone LV of 12/15LOX-/- mice at post-MI d28 and d56 compared with WT, indicating less myocyte hypertrophy. Furthermore, 12/15 LOX deletion attenuated renal inflammation through reduced NGAL and KIM-1 expression in the kidneys at d28 and d56 post-MI compared to WT. Renal microstructure assessed by histology displayed moderate mesangial expansion in glomeruli suggesting acute glomerulonephritis in WT mice during the progression of heart failure as compared with 12/15LOX–/– mice.
Conclusion: Deletion of 12/15LOX attenuated MI-associated cardiorenal inflammation by activating EP4 on pro-resolving macrophages.
Author Disclosures: V. Kain: None. K.A. Ingle: None. S.D. Prabhu: None. G.V. Halade: Research Grant; Significant; NIH-NCCAM R00AT006704.
- © 2016 by American Heart Association, Inc.