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Cardiovascular Research Advance Access first published online on February 10, 2008
This version [Corrected Proof] published online on March 11, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn035
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

MCP-1 induces cardioprotection against ischaemia/reperfusion injury: role of reactive oxygen species

Hajime Morimoto1, Masamichi Hirose2, Masafumi Takahashi1,*, Masanori Kawaguchi1, Hirohiko Ise1, Pappachan E. Kolattukudy3, Mitsuhiko Yamada2 and Uichi Ikeda1

1 Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
2 Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
3 Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL, USA

* Corresponding author. Tel: +81 263 37 3352; fax: +81 263 37 2573. E-mail address: masafumi{at}sch.md.shinshu-u.ac.jp

Aims: Monocyte chemoattractant protein-1 (MCP-1: CCL2) has been demonstrated to be involved in the pathophysiology of ischaemic heart disease; however, the precise role of MCP-1 in ischaemia/reperfusion (I/R) injury is controversial. Here, we investigated the role of cardiac MCP-1 expression on left ventricular (LV) dysfunction after global I/R in Langendorff-perfused hearts isolated from transgenic mice expressing the mouse JE-MCP-1 gene under the control of the {alpha}-cardiac myosin heavy chain promoter (MHC/MCP-1 mice).

Methods and results: In vitro experiments showed that MCP-1 prevented the apoptosis of murine neonatal cardiomyocytes after hypoxia/reoxygenation. I/R significantly increased the mRNA expression of MCP-1 in the Langendorff-perfused hearts of wild-type mice. Cardiac MCP-1 overexpression in the MHC/MCP-1 mice improved LV dysfunction after I/R without affecting coronary flow; in particular, it ameliorated LV diastolic pressure after reperfusion. This improvement was independent of both sarcolemmal and mitochondrial KATP channels. Cardiac MCP-1 overexpression prevented superoxide generation in the I/R hearts, and these hearts showed decreased expression of the NADPH oxidase family proteins Nox1, gp91phox, and Nox3 compared with the hearts of wild-type mice. Further, superoxide dismutase activity in the hearts of MHC/MCP-1 mice was significantly increased compared with that in the hearts of wild-type mice.

Conclusion: These findings suggest that cardiac MCP-1 prevented LV dysfunction after global I/R through a reactive oxygen species-dependent but KATP channel-independent pathway; this provides new insight into the beneficial role of MCP-1 in the pathophysiology of ischaemic heart diseases.

KEYWORDS Apoptosis; Cytokines; Infection/inflammation; Myocytes; Oxygen radicals

Time for primary review: 21 days


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