Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction

Shunji Hayashidani, Hiroyuki Tsutsui, Tetsuya Shiomi, Masaki Ikeuchi, Hidenori Matsusaka, Nobuhiro Suematsu, Jing Wen, Kensuke Egashira, Akira Takeshita

Research output: Contribution to journalArticle

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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-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.

Original languageEnglish
Pages (from-to)2134-2140
Number of pages7
JournalCirculation
Volume108
Issue number17
DOIs
Publication statusPublished - Oct 28 2003

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Ventricular Remodeling
Chemokine CCL2
Genetic Therapy
Myocardial Infarction
Ligation
Dilatation
Fibrosis
Heart Failure
Transforming Growth Factors
Muscle Cells
Hypertrophy
Coronary Vessels
Skeletal Muscle
Extremities
Tumor Necrosis Factor-alpha
Macrophages
Gene Expression
Messenger RNA
Genes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction. / Hayashidani, Shunji; Tsutsui, Hiroyuki; Shiomi, Tetsuya; Ikeuchi, Masaki; Matsusaka, Hidenori; Suematsu, Nobuhiro; Wen, Jing; Egashira, Kensuke; Takeshita, Akira.

In: Circulation, Vol. 108, No. 17, 28.10.2003, p. 2134-2140.

Research output: Contribution to journalArticle

Hayashidani, Shunji ; Tsutsui, Hiroyuki ; Shiomi, Tetsuya ; Ikeuchi, Masaki ; Matsusaka, Hidenori ; Suematsu, Nobuhiro ; Wen, Jing ; Egashira, Kensuke ; Takeshita, Akira. / Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction. In: Circulation. 2003 ; Vol. 108, No. 17. pp. 2134-2140.
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