Abstract 612: Differential Effects of GM-CSF and G-CSF on Infiltration of Dendritic Cells during Early Left Ventricular Remodeling after Myocardial Infarction
Background: The activation of immune system play a role in the secondary tissue injury after myocardial infarction (MI). We reported that the dendritic cell (DC), potent regulator of immunity, infiltrated into the infarcted heart. The development of DC from hematopoietic progenitor cell is differentially regulated by granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte-colony stimulating factor (G-CSF). We sought to determine the effects of these CSFs on DC infiltration and left ventricular (LV) remodeling after MI.
Methods: MI was induced by ligation of the left coronary artery in male Wistar rats. GM-CSF inducer (romurtide 200μg/kg/day, MI-GM, n=20), G-CSF (20 μg/kg/day, MI-G=20) or saline (MI-C, n=20) was administrated for 7 days. Hemodynamic and echocardiographic studies were performed at day 14. Immunohistochemical staining using monoclonal antibodies for OX62 (DC marker) and bromodeoxyuridine (BrdU) was performed at 3, 7 and 14 days after MI. Infiltrating cells were counted in infarcted (I), border (B) and non-infarcted area (NI).
Results: MI-GM had lower LV max dP/dt, higher LV end-diastolic pressure and larger LV dimensions, while MI-G had higher LV max dP/dt, lower LV end-diastolic pressure and smaller LV dimensions than MI-C at day 14. Infarct size was similar in all groups. In MI-C, DCs infiltrated into I and B peaking at day 7 (I:83±23, B:88±18 cells/mm2), but not into NI. BrdU positive DCs were observed at day 3,7,14 in B. DCs in MI-GM was increased at day 3 in I (91±16 vs 43±18 cells/mm2, p=0.002) and B (99±12 vs 59±11 cells/mm2, p=0.001) and at day 7 in I (120±15 vs 83±23 cells/mm2, p=0.041) and B (122±14 vs 88±18 cells/mm2, p=0.006) compared to MI-C. G-CSF treatment reduced infiltration of DCs at day 7 in I (55±20 vs 83±23 cells/mm2, p=0.033) and B (47±16 vs 88±18 cells/mm2, p=0.038), and at day 14 in I (24±12 vs 45±10 cells/mm2, p=0.049) and B (12±5 vs 44±20 cells/mm2, p=0.040). The mRNA expression of TGF-β1 and collagen in I at day 3 was reduced in MI-GM, but increased in MI-G.
Conclusions: G-CSF improves and GM-CSF exacerbates early post-infarction LV remodeling in association with the modulation of DC infiltration and reparative fibrosis. Modification of DC infiltration could be a new strategy for treatment of LV remodeling after MI.