Abstract 880: Improved Remodeling Following Myocardial Infarction in CCR1-KO Mice due to Modulation of Post Infarct Inflammation
Myocardial necrosis triggers a complex cytokine cascade that is not completely understood and could yet reveal promising therapeutic targets. CCR1 is a receptor for RANTES, a chemokine released from activated platelets. RANTES bound to CCR1 has been demonstrated to facilitate the adhesion of inflammatory cells to the endothelium. Here we assess the effect of CCR1 on cardiac remodeling following myocardial infarction (MI) studying CCR1 knockout (CCR1−/−) mice. Myocardial infarction (MI) was induced in CCR−/− and WT mice by proximal ligation of the LAD. Mice were sacrificed and studied at days 1, 4, 7, 14 and 21 post MI induction. While initial infarct area and area at risk did not differ between groups, infarct size decreased by day 21 in CCR1−/− mice to 11.2Â ± 1.2 % of the left ventricle (LV) while no improvement was observed in WT mice (20.6Â ± 8.4 % of LV; p < 0.05). This resulted in improved left ventricular function, as assessed by isolated heart studies according to Langendorff. Left ventricular developed pressure (LVDP) was 84.5Â ± 19.8 mmHg in CCR1−/− compared to 49.0Â ± 19.7 in WT (p < 0.01). Furthermore coronary flow reserve was improved in CCR1−/−. As possible underlying mechanism we observed an altered post infarct inflammatory pattern in CCR1−/− mice characterized by:
abrogated neutrophile infiltration;
earlier and more pronounced monocyte infiltration (peak of 1007Â ± 127 cells /mm2 infarcted area at day 7 in CCR1−/− vs. peak of 604Â ± 67 cells /mm2 infarcted area at day 14 in WT);
decreased apoptosis and increased cell proliferation in infarcted areas;
earlier myofiboblast population of the infarcted tissue (peak of 3205Â ± 251 cells /mm2 infarcted area at day 4 in CCR1−/− vs. peak of 3374Â ± 121 cells /mm2 infarcted area at day 7 in WT).
Functional and structural impaiment following MI is reduced in the absence of CCR1 due to decreased early inflammation and improved tissue healing.