Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction
Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction
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DOI：
10.1161/01.res.0000246113.82111.2d
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发表时间：
2006-10-13
影响因子：
20.1
通讯作者：
Ikeda, Uichi
中科院分区：
文献类型：
--
作者：
Morimoto, Hajime;Takahashi, Masafumi;Ikeda, Uichi
心肌梗死(MI)伴有炎症反应，导致白细胞重新聚集，继而导致心肌损伤、愈合和疤痕形成。由于单核细胞趋化蛋白-1(MCP-1)(也称为CCL2)调节单核细胞炎症反应，我们研究了心脏MCP-1过表达对心肌梗死小鼠左心功能障碍和重构的影响。在α-心肌肌球蛋白重链启动子控制下表达JE-MCP-1基因的转基因小鼠(MHC/MCP-1小鼠)用于此目的。MHC/MCP-1小鼠心肌梗死后心肌梗死面积减少，瘢痕形成减少，左心功能改善。MHC/MCP-1转基因小鼠的骨髓被Tie2/LacZ转基因小鼠所替代，但MHC/MCP-1小鼠骨髓来源的内皮细胞很少。流式细胞仪分析显示，MHC/MCP-1小鼠内皮祖细胞(CD34(+)/Flk-1(+)细胞)未见增加。MHC/MCP-1小鼠心肌梗死后可见明显的IL-6分泌、STAT3激活和左心室肥厚。此外，心肌梗死后MHC/MCP-1小鼠心肌成纤维细胞大量聚集。体外实验表明，IL-6和MCP-1联合应用可协同刺激和维持心肌细胞STAT3的激活。MCP-1、IL-6和低氧直接促进心脏成纤维细胞向肌成纤维细胞分化。结果提示，心肌MCP-1过表达可诱导巨噬细胞浸润、新生血管形成、心肌IL-6分泌和心肌成纤维细胞积聚，从而预防心肌梗死后左心功能障碍和重构。他们也提供了一个新的见解，心脏MCP-1在心肌梗死的病理生理学中的作用。
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 inMHC/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.