Abstract 848: Growth-differentiation Factor-15 Promotes Anti-inflammatory Effects And Enhances Survival After Experimental Myocardial Infarction

Abstract

Growth-differentiation factor (GDF)-15 is a stress-responsive TGF-ß related cytokine. GDF-15 plasma levels are increased and provide independent prognostic information in patients with acute coronary syndrome. After coronary ligation in mice, GDF-15 protein expression is rapidly induced and remains elevated within the infarcted myocardium for at least 7 days. We therefore postulated that GDF-15 is involved in wound healing post MI. The left descending coronary artery was ligated in male GDF-15 knock-out (KO, n=36), heterozygous (+/-, n=72) and wild-type mice (WT, n=26). Six-week mortality was significantly enhanced in KO (81%) and +/- (67%), as compared to WT mice (35%, P=0.004 by log-rank test). Four days after MI, no differences in infarct size (H.E. staining), cardiac dimensions, wall thickness, and systolic function (echocardiography) were observed (n=8 –12 per group). However, cardiac rupture was more frequent in KO (31%) as compared to WT mice (4%, P<0.01). Immunohistochemistry on day 4 demonstrated significantly elevated numbers of granulocytes (KO, 514±61/mm 2 vs. WT, 181±22/mm 2 ; P=0.003) and macrophages (KO, 176±19/mm 2 vs. WT, 89±11/mm 2 ; P=0.002) within the infarct border zone of KO mice (n=8–12 per group). This was paralleled by an increase in MMP-9 activity (in-gel zymography) within the infarct border zone (KO, 246±33% vs. WT, 100±14%; n=8–10; P=0.004); no differences in TIMP1 expression were noted between both genotypes. In vitro, pre-stimulation with GDF-15 dose-dependently inhibited the migration of human granulocytes towards the chemoattractant fMLP (10 −8 mol/L) in transwell migration chambers (3 μm pore size), control 100%; GDF-15 0.5ng/mL 78±5%, 5ng/mL 47±10%, 50ng/mL 34±10% (P<0.001). Our data identify GDF-15 as an endogenous anti-inflammatory cytokine that inhibits leukocyte infiltration, and promotes wound healing and survival after myocardial infarction.