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

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.

SUBMITTER: Kain V

PROVIDER: S-EPMC5577033 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Kain Vasundhara V Liu Fei F Kozlovskaya Veronika V Ingle Kevin A KA Bolisetty Subhashini S Agarwal Anupam A Khedkar Santosh S Prabhu Sumanth D SD Kharlampieva Eugenia E Halade Ganesh V GV

Scientific reports 20170830 1

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 inflamm ...[more]

PMID: 28855632

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Project description:Both skin wound healing and the cardiac response to myocardial infarction (MI) progress through similar pathways involving inflammation, resolution, tissue repair, and scar formation. Due to the similarities, we hypothesized that the healing response to skin wounding would predict future response to MI. Mice were given a 3-mm skin wound using a disposable biopsy punch and the skin wound was imaged daily until closure. The same set of animals was given MI by permanent coronary artery ligation 28 days later and followed for 7 days. Cardiac physiology was measured by echocardiography at baseline and MI days 3 and 7. Animals that survived until day 7 were grouped as survivors, and animals that died from MI were grouped as nonsurvivors. Survivors had faster skin wound healing than nonsurvivors. Faster skin wound healing predicted MI survival better than commonly used cardiac functional variables (e.g., infarct size, fractional shortening, and end diastolic dimension). N-glycoproteome profiling of MI day 3 plasma revealed α2-macroglobulin and ELL-associated factor 1 as strong predictors of future MI death and progression to heart failure. A second cohort of MI mice validated these findings. To investigate the clinical relevance of α2-macroglobulin, we mapped the plasma glycoproteome in patients with MI 48 h after admission and in healthy controls. In patients, α2-macroglobulin was increased 48 h after MI. Apolipoprotein D, another plasma glycoprotein, detrimentally regulated both skin and cardiac wound healing in male but not female mice by promoting inflammation. Our results reveal that the skin is a mirror to the heart and common pathways link wound healing across organs.NEW & NOTEWORTHY Faster skin wound healers had more efficient cardiac healing after myocardial infarction (MI). Two plasma proteins at D3 MI, EAF1 and A2M, predicted MI death in 66% of cases. ApoD regulated both skin and cardiac wound healing in male mice by promoting inflammation. The skin was a mirror to the heart and common pathways linked wound healing across organs.

Dataset Information

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

Publications

Resolution Agonist 15-epi-Lipoxin A<sub>4</sub> Programs Early Activation of Resolving Phase in Post-Myocardial Infarction Healing.

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