Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction
Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction
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DOI：
10.1161/01.cir.0000092890.29552.22
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发表时间：
2003-10-28
期刊：
影响因子：
37.8
通讯作者：
Takeshita, A
中科院分区：
文献类型：
--
作者：
Hayashidani, S;Tsutsui, H;Takeshita, A
背景-单核细胞趋化蛋白-1 （MCP-1）的表达增加最近在临床和实验心力衰竭中被描述。然而，其在心力衰竭中的病理生理意义尚不清楚。因此，我们确定了MCP-1是否在心肌梗死后（MI）心脏中升高，以及它的阻断是否可以减轻左室（LV）重构和衰竭的发展。方法与结果：结扎左冠状动脉，在小鼠中产生前路心肌梗死。4周后，心肌梗死小鼠左室扩张和收缩功能障碍与非梗死左室心肌细胞肥大和间质纤维化有关。结扎后1天，非梗死左室MCP-1 mRNA水平升高40倍，并持续至28天。为了阻断MCP-1信号，在结扎前3天和结扎后14天将人MCP-1基因的n端缺失突变体转染到肢体骨骼肌中。该方法提高了心肌梗死小鼠4周存活率（61% vs 87%, P < 0.05），与未治疗的心肌梗死小鼠相比，降低了左室腔扩张和收缩功能障碍、间质纤维化、巨噬细胞募集、肿瘤坏死因子-α和转化生长因子-β的心肌基因表达，尽管梗死面积以左室周长百分比计算。结论-MCP-1表达的激活有助于心肌梗死后左室重塑和心力衰竭。抗MCP-1基因治疗可能是预防心肌梗死后心力衰竭的一种有用的新策略。
Background - Increased expression of monocyte chemoattractant protein-1 (MCP-1) has recently been described in clinical and experimental failing heart. However, its pathophysiological significance in heart failure remains obscure. We thus determined whether MCP-1 is increased in post - myocardial infarction (MI) hearts and its blockade can attenuate the development of left ventricular (LV) remodeling and failure.Methods and Results - Anterior MI was produced in mice by ligating the left coronary artery. After 4 weeks, MI mice exerted LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV. MCP-1 mRNA levels were increased by 40-fold in noninfarcted LV 1 day after ligation, which persisted until 28 days. To block the MCP-1 signals, an N-terminal deletion mutant of the human MCP-1 gene was transfected into the limb skeletal muscle 3 days before and 14 days after ligation. This method improved the survival rate of mice with MI at 4 weeks (61% versus 87%, P < 0.05) as well as attenuated LV cavity dilatation and contractile dysfunction, interstitial fibrosis, recruitment of macrophages, and myocardial gene expression of tumor necrosis factor-α and transforming growth factor-β compared with the nontreated MI mice despite the comparable infarct size calculated as percent LV circumference.Conclusions - The activation of MCP-1 expression contributes to the LV remodeling and failure after MI. An anti-MCP-1 gene therapy can be a useful novel strategy for preventing post-MI heart failure.