CXCL4 Aggravates Cardiac Dilation and Mortality after Myocardial Infarction by Inducing Pro-inflammatory M1 Macrophages and Inhibiting Macrophage Phagocytosis

CXCL4 (platelet factor 4) is a pro-inflammatory chemokine whose deletion attenuates mesenteric ischemia/reperfusion injury in mice. We hypothesized that CXCL4 would exacerbate post-myocardial infarction (MI) cardiac remodeling and dysfunction. Male C57BL/6J mice (3 to 6 month old) were subjected to permanent coronary artery ligation. CXCL4 gene expression in the infarct region significantly increased from day 3 to day 7 post-MI, peaking at day 5 (all p<0.05 vs day 0). To investigate the impact of enhancing early CXCL4 levels on post-MI cardiac remodeling, mice were treated with CXCL4 (25 μg/kg/day) or saline beginning at 24 h post-MI through osmotic mini-pump infusion. Saline treated mice showed 47% survival at day 7 post-MI (7 out of 15), while CXCL4 treatment dramatically reduced survival to 10% (1 out of 10, p<0.05). Because most of the deaths occurred between days 5 to 7 post-MI, we evaluated day 5 post-MI. CXCL4 infusion resulted in a 64% increase in CXCL4 protein levels within the infarct region at ...