Resolution Agonist 15-epi-Lipoxin A₄ Programs Early Activation of Resolving Phase in Post-Myocardial Infarction...

Following myocardial infarction (MI), overactive inflammation remodels the left ventricle (LV) leading to heart failure coinciding with reduced levels of 15-epi-Lipoxin A₄ (15-epi LXA₄). However, the role of 15-epi LXA₄ in post-MI acute inflammatory response and resolving phase is unclear. We hypothesize that liposomal fusion of 15-epi-LXA₄ (Lipo-15-epi-LXA₄) or free 15-epi-LXA₄ will expedite the resolving phase in post-MI inflammation. 8 to 12-week-old male C57BL/6 mice were subjected to permanent coronary artery ligation. Lipo-15-epi-LXA₄ or 15-epi-LXA₄ (1 µg/kg/day) was injected 3 hours post-MI for (d)1 or continued daily till d5. 15-epi-LXA₄ activated formyl peptide receptor (FPR2) and GPR120 on alternative macrophages but inhibited GPR40 on classical macrophages in-vitro. The 15-epi-LXA₄ injected mice displayed reduced LV and lung mass to body weight ratios and improved ejection fraction at d5 post-MI. In the acute phase of inflammation-(d1), 15-epi-LXA₄ primes neutrophil infiltration with a robust increase of Ccl2 and FPR2 expression. During the resolving phase-(d5), 15-epi-LXA₄ initiated rapid neutrophils clearance with persistent activation of FPR2 in LV. Compared to MI-control, 15-epi-LXA₄ injected mice showed reduced renal inflammation along with decreased levels of ngal and plasma creatinine. In summary, 15-epi-LXA₄ initiates the resolving phase early to discontinue inflammation post-MI, thereby reducing LV dysfunction.