Abstract 1274: Syndecan-4 Pathway Interception Reduces Infarct Size After Myocardial Ischemia And Impacts On Remodelling

Abstract

Objectives: Reperfusion injury after myocardial ischemia is governed by leukocyte recruitment. Syndecan-4 (SDC4) has been shown to be a major regulator of cell-cell and cell-matrix interactions. We tested if the SDC4-pathway impacts on myocardial necrosis, tissue loss and remodeling in mouse models of myocardial ischemia/infarction. In addition we analyzed the role of SDC4 in leukocyte recruitment in vitro and in mouse peritonitis. Methods: Syndecan4-deficient (SDC4 −/− ) or wildtype (WT) mice were subjected to transient (30 min; MI/R) or permanent (MI) LAD-ligation. In MI/R, after reperfusion for 24h, infarct size was measured by lack of TTC-staining. The extracellular SDC4-domain (ED-SDC4) was systemically overexpressed by hydrodynamic transfection (HDTF). Echocardiography revealed LV-function 4 days after MI(/R). Neutrophil extravasation was tested by lavaging mice 4h after IP-injection of thioglycollate. Adhesion of SDC4 −/− - or WT-PMN to resting or TNFα-activated, SDC4-siRNA-treated mouse endothelioma cells (EC) was tested in an adhesion assay. Results: Infarctions after MI/R were 43±7% larger in SDC4 −/− compared to WT (p<0.01, n=8). ED-SDC4-HDTF reduced infarct size by 27±4% (p<0.05, n=6). LV-function after MI was significantly worse in WT than SDC-4-KO (EF pre-post : −45±7% and −55±8%; p<0.05). In SDC4 −/− LV-dilation after MI was significantly ameliorated (EDV post-pre : 28±7μl vs. 39±8μl, SDC4 −/− vs WT, p<0.05). Emigration of GR-1 + -PMN of SDC4 −/− was increased by 2±0.5-fold in peritoneal lavages (n=6, p<0.05). SDC4 knock down (−80% in RT-PCR) in EC augmented adhesion of PMNs to resting EC by 41±8% and TNFα-activated EC by 20±5%. Adhesion of SDC-4-KO-PMN to resting and TNFα-activated EC was increased by 22±5% and 16±5%. SDC-4-KO-PMN adhesion to activated SDC4 knock down-EC was increased by 40±5% (p<0.05, n=3). Conclusion: SDC-4 is a powerful regulator of leukocyte-endothelial interactions and directly links molecular events driving myocardial necrosis and dilatative remodelling. Lack of SDC-4 increases, soluble SDC4 decreases infarct size. SDC4-deficiency reduces dilatative remodelling after MI. Therefore SDC4 beneficially influences early tissue necrosis after ischemia but adversely influences cardiac remodelling.