Abstract 1215: Fcγ Receptor Engagement Mediates Differentiation of Cardiac Fibroblast Precursor Cells
We have previously shown that repetitive brief coronary occlusion and reperfusion of murine myocardium induces a MCP-1 dependent fibrotic cardiomyopathy (I/RC) in the absence of cardiomyocyte cell death that is mediated by activated CD34+, CD45+ myofibroblasts of bone marrow-derived, blood-borne origin. We also found that the pentraxin serum amyloid P (SAP), a serum factor closely related to C-reactive protein that binds to the receptors for the Fc portion of IgG (Fcγ receptors), markedly reduces activated CD34+, CD45+ myofibroblasts in the injured heart resulting in preservation of cardiac structure and function. Further analysis revealed that this was not due to SAP-mediated attenuation of I/RC-induced MCP-1 expression. To investigate the molecular mechanisms by which SAP reduced cardiac fibrosis, we subjected C57BL/6 wild type and Fcγ receptor gamma chain (a common membrane signaling component of several Fcγ receptors) knock-out (KO) mice to I/RC with daily administration of either 50 μg murine SAP, or equimolar amounts of albumin (control). In Fcγ receptor gamma chain KO mice we observed that SAP failed to inhibit the development of fibrosis and cardiac dysfunction, and did not diminish the amount of α-smooth muscle actin+, CD34+ and CD45+ cells which were typical for the I/RC heart. We have subsequently found CD45+ myofibroblasts in non-scar sections of human ischemic cardiomyophathy. In vitro assays in which human peripheral blood mononuclear cells migrated through HUVEC in response to MCP-1 revealed that cell migration was not inhibited by SAP. However, the amount of cells that differentiated into fibroblasts after cell migration was significantly reduced when SAP was added to the PMNC suspension before endothelial transmigration. Adding SAP to cells after successful migration did not inhibit fibroblast differentiation. These data indicate that SAP inhibits the differentiation of a blood-borne, myeloid cell population into activated fibroblasts by signaling through one or more Fcγ receptors. We hypothesize that the Fcγ receptors may represent a critical mechanistic link between cardiac fibrosis and the activated immune system.