Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice mimics ischemic preconditioning through SAPK/JNK1/2 activation.
OBJECTIVE
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-alpha, 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-alpha (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-alpha, 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.


CONCLUSIONS
Overexpression of MCP-1 by cardiomyocytes causes chronic infiltration and activation of leukocytes, resulting in elevated TNF-alpha 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.
Martire
Alessandra
A
Department of Experimental Cardiology, Max-Planck-Institute, Benekestrasse 2, D-61231 Bad Nauheim, Germany. a.martire@kerckhoff.mpg.de
Fernandez
Borja
B
Buehler
Alexandra
A
Strohm
Claudia
C
Schaper
Jutta
J
Zimmermann
René
R
Kolattukudy
Pappachan E
PE
Schaper
Wolfgang
W
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism*; D006352:Heart Ventricles / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009203:Myocardial Infarction / Q000276:immunology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018932:Chemokine CCL2; D014409:Tumor Necrosis Factor-alpha; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases