Cardiac Overexpression of Monocyte Chemoattractant Protein-1 in Transgenic Mice Prevents Cardiac Dysfunction and Remodeling After Myocardial Infarction

Abstract

Abstract-Myocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes and subsequent myocardial damage, healing, and scar formation. Because monocyte chemoattractant protein-1 (MCP-1) (also known as CCL2) regulates monocytic inflammatory responses, we investigated the effect of cardiac MCP-1 overexpression on left ventricular (LV) dysfunction and remodeling in a murine MI model. Transgenic mice expressing the mouse JE-MCP-1 gene under the control of the ␣-cardiac myosin heavy chain promoter (MHC/MCP-1 mice) were used for this purpose. MHC/MCP-1 mice had reduced infarct area and scar formation and improved LV dysfunction after MI. These mice also showed induction of macrophage infiltration and neovascularization; however, few bone marrow-derived endothelial cells were detected in MHC/MCP-1 mice whose bone marrow was replaced with that of Tie2/LacZ transgenic mice. Flow cytometry analysis showed no increase in endothelial progenitor cells (CD34 ϩ /Flk-1 ϩ cells) in MHC/MCP-1 mice. Marked myocardial interleukin (IL)-6 secretion, STAT3 activation, and LV hypertrophy were observed after MI in MHC/MCP-1 mice. Furthermore, cardiac myofibroblasts accumulated after MI in MHC/MCP-1 mice. In vitro experiments revealed that a combination of IL-6 with MCP-1 synergistically stimulated and sustained STAT3 activation in cardiomyocytes. MCP-1, IL-6, and hypoxia directly promoted the differentiation of cardiac fibroblasts into myofibroblasts. Our results suggest that cardiac overexpression of MCP-1 induced macrophage infiltration, neovascularization, myocardial IL-6 secretion, and accumulation of cardiac myofibroblasts, thereby resulting in the prevention of LV dysfunction and remodeling after MI. They also provide a new insight into the role of cardiac MCP-1 in the pathophysiology of MI. Key Words: cytokines Ⅲ heart failure Ⅲ hypertrophy Ⅲ inflammation Ⅲ myocardial infarction M yocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes and subsequent myocardial damage, healing, and scar formation. 1 Recruitment and activation of monocytes/macrophages in the infarcted myocardium have been shown to contribute importantly to the processes that occur after MI. The activated macrophages lead to the release of cytokines and proteinases, which can induce further inflammation and left ventricular (LV) remodeling. Meanwhile, recent evidence indicates that some endothelial progenitor cells (EPCs) are derived from monocytic lineage cells and participate in neovascularization in ischemic tissues. [2][3][4] Moreover, monocytic-derived EPCs secrete a large amount of angiogenic factors such as the vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), 4 thereby suggesting that monocytes/macrophages could improve LV dysfunction and remodeling after MI.Chemokines are a family of potent chemotactic cytokines that regulate locomotion and trafficking of leukocytes in basal and inflammatory processes; however, it has been rece...

Macrophages are required for neonatal heart regeneration

“…Recent studies demonstrated that disruption of C/ EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function (19). However, both positive (20)(21)(22) and negative (23)(24)(25)(26) correlations between tissue remodeling and monocytes, and their lineage descendant macrophages, have been reported. CCL2, a chemokine that recruits and activates monocytes, seems to play a dual role in MI.…”

“…CCL2, a chemokine that recruits and activates monocytes, seems to play a dual role in MI. Targeted deletion of the CCL2 receptor (CCR2) improved left ventricular dilation and dysfunction (20,21), while cardiac overexpression of CCL2 also improved outcome (23) by inducing macrophages infiltration, angiogenesis, myocardial IL-6 secretion, and accumulation of cardiac myofibroblasts. Biphasic recruitment of Ly-6C hi and Ly-6C lo monocyte subsets from the spleen also promotes infarct healing (26)(27)(28)(29).…”

Novel anti-inflammatory mechanisms ofN-Acetyl-Ser-Asp-Lys-Pro in hypertension-induced target organ damage

“…There is evidence that inflammation contributes to end organ damage (20). We have shown that in ANG IIinduced hypertension (32), as well as in renovascular hypertension (25,35), mineralocorticoid-salt hypertension (26,28), spontaneously hypertensive rats (9), and heart failure postmyocardial infarction (24), N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) not only prevents but also reverses inflammation, cell proliferation, and fibrosis in the heart and kidney.…”

MCPIP mediates preconditioning protection against ischemia

“…Evidence suggested that SAPK/JNK activation was involved in the preconditioning effects 1 . Prevention of left ventricle (LV) dysfunction and remodeling in the mice with cardiomyocyte-targeted expression of MCP-1 was found to involve enhanced neovascularization and promotion of differentiation of cardiac fibroblasts into myofibroblasts 2 . Brain preconditioning by inflammatory inducer has also been reported [3][4][5] .…”

“…This protection is called preconditioning, a phenomenon which brief episodes of a sublethal insult induce robust protection against subsequent lethal injuries. For example, cardiomyocyte-targeted expression of monocyte chemotactic protein-1 (MCP-1) showed such a preconditioning protective effect against experimental myocardial ischemic injury 1,2 . Coronary occlusion followed by reperfusion showed that the animals expressing MCP-1 had a much smaller infarct size when compared to the wild type 1 .…”