Open AccessResolution Agonist 15-epi-Lipoxin A4 Programs Early Activation of Resolving Phase in Post-Myocardial Infarction Healing
Author(s) -
Vasundhara Kain,
Fei Liu,
Veronika Kozlovskaya,
Kevin A. Ingle,
Subhashini Bolisetty,
Anupam Agarwal,
Santosh A. Khedkar,
Sumanth D. Prabhu,
Eugenia Kharlampieva,
Ganesh V. Halade
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-10441-8
Subject(s) - inflammation , lipoxin , myocardial infarction , medicine , ejection fraction , receptor , agonist , cardiology , endocrinology , heart failure
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.