Abstract 14885: CXCL4 Aggravates Mortality and Left Ventricular Dilation Following Myocardial Infarction by Polarizing Macrophages to a Pro-inflammatory M1 Phenotype
CXCL4 deletion attenuates atherosclerosis and mesenteric ischemia/reperfusion injury in mice. CXCL4 roles following myocardial infarction (MI) have not been evaluated. We hypothesized that CXCL4 would exacerbate post-MI wound healing and cardiac dysfunction. Male C57BL/6J mice (n=82) of 3-6 months old were subjected to permanent coronary artery ligation. CXCL4 gene expression significantly increased after MI, peaking at day 5 (p<0.05 vs day 0). To investigate whether CXCL4 exacerbates the inflammatory response, the mice were treated with 5, 25, or 50 μg/kg/day CXCL4 or saline at 24 hours post-MI through osmotic mini-pump as an overexpression strategy. Saline treated mice showed 47% survival at day 7 post-MI (7 out of 15), while CXCL4 treatment with all 3 doses dramatically reduced the survival rate to 10% (1 out of 10, p<0.05). Autopsy evaluation revealed that 50% (4 of 8) of saline treated mice died of cardiac rupture, while CXCL4 treatment (50 μg/kg/day) showed 89% rupture rate (8 of 9). The infarct area was similar between saline and CXCL4 treated surviving mice (53±2% for saline and 53±4% for CXCL4, p=0.95). Compared to the saline group, CXCL4 treated mice showed significantly higher end-systolic and end-diastolic volumes (both p<0.05), indicating that CXCL4 exacerbated left ventricular dilation. Out of 84 inflammatory genes measured, CXCL4 treatment resulted in the decreased expression of Ccl3 and Ltb and increased expression of Ccr4 and Cxcl11 (all p<0.05 compared to saline treatment), indicating very specific signaling targets. In vitro, CXCL4 (5 μg/mL, 4 hour stimulation) polarized macrophages to a pro-inflammatory M1 phenotype, evidenced by upregulation of M1 markers (Ccl3, Ccl5, Il1β, and Il6, all p<0.05), and by downregulation of M2 marker Cd206 (p<0.05). In conclusion, CXCL4 exacerbated mouse death and left ventricular dilation post-MI by polarizing macrophages towards a pro-inflammatory M1 subtype.
Author Disclosures: Y. Ma: None. A. Yabluchanskiy: None. R. Clark: None. P.L. Cannon: None. E.R. Flynn: None. Y. Jin: Research Grant; Significant; NIH 1R03EB009496, SC2HL101430. M.L. Lindsey: Research Grant; Significant; NIH/NHLBI HHSN 268201000036C (N01-HV-00244), R01 HL075360, PPG HL051971, GM104357, the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award 5I01BX000505.
- © 2014 by American Heart Association, Inc.