Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction.
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 alpha-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+/Flk-1+ 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.
Morimoto
Hajime
H
Department of Cardiovascular Medicine and Regeneration, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
Takahashi
Masafumi
M
Izawa
Atsushi
A
Ise
Hirohiko
H
Hongo
Minoru
M
Kolattukudy
Pappachan E
PE
Ikeda
Uichi
U
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002196:Capillaries / Q000503:physiopathology; D006332:Cardiomegaly / Q000209:etiology; D002454:Cell Differentiation; D018932:Chemokine CCL2 / Q000378:metabolism / Q000502:physiology*; D002921:Cicatrix / Q000473:pathology; D003331:Coronary Vessels / Q000503:physiopathology; D016207:Cytokines / Q000502:physiology; D004452:Echocardiography; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D018836:Inflammation Mediators / Q000502:physiology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D018932:Chemokine CCL2; D016207:Cytokines; D018836:Inflammation Mediators; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse