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Resolution Agonist 15-epi-Lipoxin A(4) Programs Early Activation of Resolving Phase in Post-Myocardial Infarction Healing
Following myocardial infarction (MI), overactive inflammation remodels the left ventricle (LV) leading to heart failure coinciding with reduced levels of 15-epi-Lipoxin A(4) (15-epi LXA(4)). However, the role of 15-epi LXA(4) in post-MI acute inflammatory response and resolving phase is unclear. We...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577033/ https://www.ncbi.nlm.nih.gov/pubmed/28855632 http://dx.doi.org/10.1038/s41598-017-10441-8 |
Sumario: | Following myocardial infarction (MI), overactive inflammation remodels the left ventricle (LV) leading to heart failure coinciding with reduced levels of 15-epi-Lipoxin A(4) (15-epi LXA(4)). However, the role of 15-epi LXA(4) in post-MI acute inflammatory response and resolving phase is unclear. We hypothesize that liposomal fusion of 15-epi-LXA(4) (Lipo-15-epi-LXA(4)) or free 15-epi-LXA(4) 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-LXA(4) or 15-epi-LXA(4) (1 µg/kg/day) was injected 3 hours post-MI for (d)1 or continued daily till d5. 15-epi-LXA(4) activated formyl peptide receptor (FPR2) and GPR120 on alternative macrophages but inhibited GPR40 on classical macrophages in-vitro. The 15-epi-LXA(4) 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-LXA(4) primes neutrophil infiltration with a robust increase of Ccl2 and FPR2 expression. During the resolving phase-(d5), 15-epi-LXA(4) initiated rapid neutrophils clearance with persistent activation of FPR2 in LV. Compared to MI-control, 15-epi-LXA(4) injected mice showed reduced renal inflammation along with decreased levels of ngal and plasma creatinine. In summary, 15-epi-LXA(4) initiates the resolving phase early to discontinue inflammation post-MI, thereby reducing LV dysfunction. |
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