Abstract P3089: Selective Activation Of Cardiac Macrophages To Study Injury And Repair

Abstract

Objective: Pathophysiological inflammatory responses play an important role during ischemia-mediated heart injury and remodeling, where monocytes and macrophages appear to be critically involved. Cardiac macrophages are generally classified as a recruited, monocyte-derived subset that is Ccr2 + and a tissue resident subset that is typically Ccr2 - . Recent studies have shown that these two subsets have divergent functions with Ccr2 - macrophages being pro-regenerative while Ccr2 + macrophages are pro-inflammatory. Here we selectively manipulated the content and/or activation of these two macrophage subsets in the heart. Methods and Results: To study the function of Ccr2 + cardiac macrophages in the heart, we have overexpressed Ccl-2 (Mcp-1) ligand specifically in cardiomyocytes by using adeno-associated virus serotype-9 (AAV9) mediated gene transfer. Postnatal day 4 (p4) Ccr2 RFP/+ pups were injected with either AAV9-Ccl-2 or AAV9-control. At two months of age, we observed increased Ccl-2 transcripts and protein expression in the heart as measured by qRT-PCR and ELISA, respectively. By quantifying immune cells using flow cytometry, we observed increased infiltration of Ccr2 + macrophages (CD45 + CD11b + CD64 + ) in the hearts of AAV9-Ccl2 injected mice compared to controls. However, echocardiography analysis revealed no change in cardiac function in adult Ccl-2 overexpressed mice. Moreover, the recruitment of Ccr2 + macrophages into the myocardium did not cause fibroblast expansion or activation. Conclusion: Our results show that cardiomyocyte-specific overexpression of Ccl-2 induces profound infiltration of Ccr2 + macrophages into the myocardium but this did not alter cardiac function or cause fibrosis at two or six months of age.