Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 10, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn035
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MCP-1 Induces Cardioprotection against Ischaemia/Reperfusion Injury: Role of Reactive Oxygen Species
1 Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, Matsumoto, Japan
2 Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan
3 Burnett College of Biomedical Sciences, University of Central Florida, Orlando, USA
Correspondence: Masafumi Takahashi, MD, PhD, Division of Cardiovascular Sciences, Department of Organ Regeneration, Shinshu University Graduate School of Medicine. 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. Tel/Fax: +81-263-37-3352/ +81-263-37-2573 E-mail: masafumi{at}sch.md.shinshu-u.ac.jp
Aim: 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 
-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.
Conclusions: 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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