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Resolution Agonist 15‐epi‐Lipoxin A 4 Directs FPR2 to Expedite Healing Phase Post‐Myocardial Infarction
Author(s) -
Kain Vasundhara,
Liu Fei,
Kozlovskaya Veronika,
Ingle Kevin A,
Khedkar Santosh,
Prabhu Sumanth D,
Kharlampieva Eugenia,
Halade Ganesh V
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.306.2
Subject(s) - lipoxin , inflammation , chemistry , myocardial infarction , agonist , medicine , pharmacology , receptor , endocrinology
Post‐myocardial infarction (MI), overactive inflammation remodels the left ventricle (LV) to cause heart failure, marked with reduced levels of resolution markers such as 15‐epi‐Lipoxin A 4 (15‐epi LXA 4 ). However, the role of 15‐epi LXA 4 in acute inflammatory response and resolving phase post‐MI is unclear. We hypothesize that 15‐epi‐LXA 4 with liposomal fusion (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 (1ug/kg/day) was injected 3 hours post‐MI for day (d)1 or until d5. Mice with no treatment served as MI‐control and mice with no‐MI were used as d0 naïve controls. In‐vitro experiment using peritoneal macrophages showed 15‐epi‐LXA 4 activated formyl peptide receptor (FPR2/ALX) and GPR120 on alternative macrophages, but inhibited GPR40 on classical macrophages. The 15‐epi‐LXA 4 injected mice displayed reduced LV‐ and lung mass‐to‐body weight ratios and increased fractional shortening at d5 post‐MI. In acute phase (d1), 15‐epi‐LXA 4 primes neutrophil infiltration with a robust increase of Ccl2 ( FPR2/ALX) (all p<0.05) expression compared to MI‐control group. During resolving phase (d5), 15‐epi‐LXA 4 initiated the rapid clearance of neutrophils with persistent activation of FPR2/ALX in both LV and spleen with inhibition of GPR40 . 15‐epi‐LXA 4 increased transcripts of proresolving markers Arg‐1 and Ym‐1 at d5 post‐MI ( all p<0.05) in the infarcted LV. Post‐MI splenic activation and reduced kidney inflammation was marked by an increase in expression of Mrc‐1/CD206 and Ym‐1 ( both p<0.05) as well as a decreased level of NGAL and plasma creatinine, respectively in 15‐epi‐LXA 4 group. In summary, 15‐epi‐LXA 4 initiates the resolving phase early to remit uncontrolled inflammation post‐MI, thereby reduced LV dysfunction. Support or Funding Information This work was supported by grants from National Institutes of Health (NIH)‐NCCAM R00AT006704, Michigan Regional Comprehensive Metabolomics Resource Core and UAB start‐up fund to G.V.H