Abstract 1375: Cardiac Overexpression of Monocyte Chemoattractant Protein-1 in Transgenic Mice Prevents Cardiac Dysfunction and Remodeling After Myocardial Infarction
Background: Myocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes, and subsequent myocardial damage, healing, and scar formation. Since monocyte chemoattractant protein-1 (MCP-1; CCL2) regulates monocytic inflammatory responses, we investigated the effect of cardiac MCP-1 overexpression on left ventricular (LV) dysfunction and remodeling in a model of MI using transgenic mice expressing mouse JE-MCP-1 gene under the control of the α-cardiac myosin heavy chain promoter (MHC/MCP-1 mice).
Methods and Results: Total 60 mice were used in this study. MHC/MCP-1 mice had reduced infarct area (p<0.01) and scar formation (p<0.01) and improved LV dysfunction after MI (%FS: 45.5 vs. 35.3, p<0.01) at 14 days after MI. MHC/MCP-1 mice also showed induction of macrophage infiltration (F4/80) and neovascularization (CD31) in the border area of MI; however, few bone marrow-derived endothelial cells (LacZ-positive cells) were detected in MHC/MCP-1 mice whose bone marrow was replaced with that of Tie2/LacZ transgenic mice. Flow cytometric analysis showed that monocytes (Mac-1+/Gr-1−) and hematopoietic progenitor cells (CD34+), but not endothelial progenitor cells (EPCs: CD34+/Flk-1+), were increased in peripheral circulation after MI in MHC/MCP-1 mice. Marked myocardial interleukin (IL)-6 secretion, STAT3 phosphorylation, and LV hypertrophy were observed after MI in MHC/MCP-1 mice although these changes were not observed at baseline conditions. Furthermore, cardiac myofibroblasts were accumulated after MI in MHC/MCP-1 mice. In vitro experiments revealed increased and sustained phosphorylation of STAT3 in response to IL-6 (10 ng/mL) combined with MCP-1 (10 ng/mL) in cardiomyocytes. MCP-1 and hypoxia directly promoted differentiation of cardiac fibroblasts into myofibroblasts.
Conclusion: Our results suggest that cardiac overexpression of MCP-1 induced macrophage infiltration, neovascularization, myocardial IL-6 secretion, and accumulation of cardiac myofibroblasts, resulting in the prevention of LV dysfunction and remodeling after MI, and provide a new insight into the role of cardiac MCP-1 in the pathophysiology of MI.