© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice mimics ischemic preconditioning through SAPK/JNK1/2 activation
aDepartment of Experimental Cardiology, Max-Planck-Institute, Benekestrasse 2, D-61231 Bad Nauheim, Germany
bKerckhoff-Clinic, Bad Nauheim, Germany
cNeurobiotechnology Center, The Ohio State University, Columbus, OH, USA
* Corresponding author. Tel.: +49-6032-705-402; fax: +49-6032-705-419. a.martire{at}kerckhoff.mpg.de
Objective and methods: Although a beneficial association between innate immunity and ischemic preconditioning has recently been proposed, the mechanisms responsible for this link are poorly understood. To test the hypothesis that pro-inflammatory cytokines have a beneficial role in the activation of the cell survival pathway mediated by ischemic preconditioning, we have studied transgenic mice with cardiac myocyte specific overexpression of murine monocyte chemoattractant protein-1 (MCP-1). The resistance to ischemia was studied by performing 45-min (with or without injection of the SAPK/JNKs inhibitor D-JNKI1) and 3-day left coronary artery occlusions as well as 45-min left coronary artery occlusion followed by 3 days of reperfusion. In addition, quantitative Western blot analyses for TNF-
, and SAPK/JNK1/2, ERK1/2 and p38 activity were performed. Results: Infarct size, expressed in percent of either the risk area or the left ventricle, was reduced in transgenic mice when compared with control after both, 45-min (14.7±2.6% vs. 52.0±2.4%; P<0.05) and 45-min occlusion followed by 3 days of reperfusion (23.2±1.8% vs. 30.0±1.8%; P<0.05) but it was not significantly different for 3-day occlusion. Western blot analyses showed significantly increased levels of TNF- (1.8-fold) and phosphorylated-SAPK/JNK1/2 (1.5-fold) in transgenic hearts. Phosphorylated-ERK1/2, and phosphorylated-p38 levels were unchanged. Immunohistochemistry revealed that in transgenic mice monocytes/macrophages, lymphocytes, and fibroblasts are the source of TNF-, whereas myocytes have increased phosphorylated-SAPK/JNK1/2 levels. In addition, injection of the SAPK/JNKs inhibitor D-JNKI1 partially abrogated the cardioprotective effect observed in untreated transgenic mice. Conclusion: Overexpression of MCP-1 by cardiomyocytes causes chronic infiltration and activation of leukocytes, resulting in elevated TNF- secretion and SAPK/JNK1/2 activation. The activation of this pathway is in part responsible for the preconditioning effect of MCP-1 overexpression. These results show a possible beneficial link between innate immunity and ischemic preconditioning through MAP-kinase activation.
KEYWORDS Cytokines; Ischemia; Leukocytes; Preconditioning; Signal transduction
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