Profibrotic alternatively activated M2 macrophages are associated with increased severity of dilated cardiomyopathy in male BALB/c mice with cosackievirus B3-induced autoimmune myocarditis (135.20)

Abstract Current research has shown heart disease as the leading killer in the US. Autoimmune myocarditis (AM) progresses to dilated cardiomyopathy (DCM) and occurs at a higher incidence in males. In order to study sex differences in AM we inoculated BALB/c mice with 103 PFU of coxsackievirus B3 with cardiac myosin ip to induce autoimmunity. At d10 post infection males develop severe myocarditis that progresses to DCM at d35. We investigated functional endpoints of DCM by echocardiography at d90 and found that males developed significantly more severe DCM. To investigate sex differences further we conducted a microarray comparing infected males and females. Approximately 500 genes were significantly up regulated in males. Genes increased with a > 1.5 fold change fell into categories associated with Th2 responses, M2 macrophages (Macs), and extracellular matrix (ECM) remodeling. We showed previously that male cardiac CD11b+ GR1+ Macs express the mannose receptor (MR), TLR4, caspase-1 and IL-1β. This microarray confirmed that males have increased M2 markers including the MR, CD14 and IL-33. We also found upregulation of ECM remodeling genes including proteoglycan-4, timp-1 and tenascin-C indicating cardiac remodeling. Th2 responses are known to increase ECM remodeling and can drive differentiation of Macs to an M2 phenotype. Our data suggests that Th2 associated profibrotic M2 Macs may increase cardiac remodeling in males during AM resulting in DCM. Funded by NIH-HL-087033.