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. 2003 Oct 28;108(17):2134-40.
doi: 10.1161/01.CIR.0000092890.29552.22. Epub 2003 Sep 29.

Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction

Shunji Hayashidani  1 , Hiroyuki Tsutsui, Tetsuya Shiomi, Masaki Ikeuchi, Hidenori Matsusaka, Nobuhiro Suematsu, Jing Wen, Kensuke Egashira, Akira Takeshita
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Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction

Shunji Hayashidani et al. Circulation. .

Abstract

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-alpha and transforming growth factor-beta 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.

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