title: Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction.
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 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.
authors.affiliation: Department of Cardiovascular Medicine and Regeneration, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Morimoto
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Izawa
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Ise
authors.forename: Minoru
authors.initials: M
authors.lastname: Hongo
authors.forename: Pappachan E
authors.initials: PE
authors.lastname: Kolattukudy
authors.forename: Uichi
authors.initials: U
authors.lastname: Ikeda
mesh_terms: 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
chemical_list: D018932:Chemokine CCL2; D016207:Cytokines; D018836:Inflammation Mediators; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse