Abstract
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.
Highlights
Authors Vasundhara Kain, Fei Liu, Veronika Kozlovskaya, Kevin A
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-myocardial infarction (MI) inflammation. 8 to 12-week-old male C57BL/6 mice were subjected to permanent coronary artery ligation
Figure 1. 15-epi-LXA4 upregulates macrophage FPR2 and GPR120 and limits TGF-β-mediated myofibroblast differentiation. (A) In-vitro study design using peritoneal macrophages stimulated with LPS (1 μg/ml) + IFNγ (20 ng/ml) to differentiate in M1 macrophage or IL-4 (20 ng/ml) + IL-13(20 ng/ml) to differentiate into M2 macrophage and cardiac fibroblast isolated from male C57BL/6 mice (6–8 weeks of age) treated with TGF-β for myofibroblast differentiation. mRNA expression of (B) FPR2 (C) GPR120 (D) GPR40 on proinflammatory (M1) and proresolving (M2) peritoneal macrophages with and without 15-epi-LXA4 (100 nM) treatment. *p < 0.001 vs. naïve macrophages, $p < 0.05 vs 15-epi-LXA4 treatment
Summary
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). The role of 15-epi LXA4 in post-MI acute inflammatory response and resolving phase is unclear. During the resolving phase-(d5), 15-epi-LXA4 initiated rapid neutrophils clearance with persistent activation of FPR2 in LV. We hypothesize that the stable form of LXA4; 15-epi-LXA4 with liposomal fusion (Lipo-15-epi-LXA4) or free 15-epi-LXA4 would initiate the resolving phase at the precise time in post-MI healing to limit cardiac remodeling and subsequent heart failure. Our in-vitro and in-vivo results indicate that post-MI treatment of pure 15-epi-LXA4 or liposomal 15-epi-LXA4 initiates the early resolving phase, suggesting a therapeutic potential of the lipoxin biomolecule to delay MI-induced cardiorenal pathology
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