Monocyte chemoattractant protein-1 (MCP-1) transgenic mice : lessons from cardioprotection against ischemia to autoimmune inflammatory diseases
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To test both, the hypothesis that moderate productions of pro-inflammatory cytokines have a beneficial role in the activation of the cell survival pathway mediated by ischemic preconditioning, and that prolonged cytokines production has a detrimental effect, we have studied transgenic (TG) mice with cardiac myocyte specific overexpression of murine monocyte chemoattractant protein-1 (MCP-1). The resistance to ischemia was studied in adult mice by performing 45-min (with or without injection of the SAPK/JNKs inhibitor D-JNKI1) and 3-day left coronary artery occlusions (CAO)as well as 45-min occlusion followed by 3 days of reperfusion (45-min CAO+3-day R). Quantitative Western blot analyses for TNF-alpha, and SAPK/JNK1/2, ERK1/2, p-38 activity were performed. In addition, immunofluorescence for ubiquitin (ubi, autophagic cell death), complement 9 (C9, necrosis), and MHC class II (autoimmunity) antibodies and TUNEL (apoptosis) method were performed. Infarct size was reduced in TG mice as compared to control (WT) mice after 45-min CAO (14.7±2.6% vs. 52.0±2.4%; p<0.05) and 45-min CAO+3-day R (23.2±1.8% vs. 30.0±1.8%; p<0.05) but not after 3-day CAO. Phosphorylated-(p)-ERKs, and p-p-38 levels were unchanged. P-SAPK/JNK1/2 (expressed by myocytes) and TNF-alpha (expressed by activated inflammatory cells) levels were increased in TG mice compared to WT. In addition, injection of D-JNKI1 partially abrogated the cardioprotective effect observed in untreated TG mice. Finally, quantitative data expressed as percentage of total number of myocytes are reported for TG and WT mice. Ubi: 0.64±0.11 vs. 0; C9: 0.34±0.029 vs. 0; MHC II: 0.27±0.026 vs. 0; TUNEL: 0 vs. 0. Moderate overexpression of MCP-1 causes chronic infiltration and activation of leukocytes resulting in cardioprotection against ischemia through SAPK/JNKs activation in adult mice. Prolonged MCP-1 overexpression induces in old mice cardiomyopathy characterized by different types of cell death: autoimmunity, autophagy, necrosis but not apoptosis, and premature death.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Cardiovascular Research, 57 (2003), S. 523-534