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lüll C/EBP homologous protein deficiency attenuates myocardial reperfusion injury by inhibiting myocardial apoptosis and inflammation Miyazaki Y; Kaikita K; Endo M; Horio E; Miura M; Tsujita K; Hokimoto S; Yamamuro M; Iwawaki T; Gotoh T; Ogawa H; Oike YArterioscler Thromb Vasc Biol 2011[May]; 31 (5): 1124-32OBJECTIVE: To investigate whether and how the endoplasmic reticulum (ER) stress-induced, CCAAT/enhancer-binding protein-homologous protein (CHOP)-mediated pathway regulates myocardial ischemia/reperfusion injury. METHODS AND RESULTS: Wild-type and chop-deficient mice underwent 50 minutes of left coronary artery occlusion followed by reperfusion. Expression of chop and spliced x-box binding protein-1 (sxbp1) mRNA was rapidly and significantly increased in reperfused myocardium of wild-type mice. chop-deficient mice exhibited markedly reduced injury size after reperfusion compared with wild-type mice, accompanied by a decreasing number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cardiomyocytes. Interestingly, myocardial inflammation, as assessed by expression of inflammatory cytokines and chemokines and numbers of infiltrated inflammatory cells, was also attenuated in chop-deficient mice. Moreover, expression of interleukin-6 mRNA in response to lipopolysaccharide was enhanced by simultaneous stimulation with thapsigargin, a potent ER stressor, in wild-type cardiomyocytes but not in chop-deficient cardiomyocytes. Finally, we found that superoxide was produced in reperfused myocardium and that intravenous administration of edaravone, a free radical scavenger, immediately before reperfusion significantly suppressed the superoxide overproduction and subsequent expression of sxbp1 and chop mRNA, followed by reduced injury size in wild-type mice. CONCLUSIONS: The ER stress-induced, CHOP-mediated pathway, which is activated in part by superoxide overproduction after reperfusion, exacerbates myocardial ischemia/reperfusion injury by inducing cardiomyocyte apoptosis and myocardial inflammation.|*Apoptosis/drug effects[MESH]|Animals[MESH]|Antipyrine/analogs & derivatives/pharmacology[MESH]|Cells, Cultured[MESH]|Chemokines/metabolism[MESH]|Cytokines/metabolism[MESH]|DNA-Binding Proteins/genetics/metabolism[MESH]|Disease Models, Animal[MESH]|Edaravone[MESH]|Endoplasmic Reticulum/drug effects/immunology/*metabolism[MESH]|Free Radical Scavengers/pharmacology[MESH]|Gene Expression Regulation[MESH]|Inflammation Mediators/metabolism[MESH]|Inflammation/genetics/immunology/metabolism/pathology/*prevention & control[MESH]|Male[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Mice, Knockout[MESH]|Myocardial Reperfusion Injury/genetics/immunology/metabolism/pathology/*prevention & control[MESH]|Myocardium/immunology/*metabolism/pathology[MESH]|RNA Splicing[MESH]|RNA, Messenger/metabolism[MESH]|Regulatory Factor X Transcription Factors[MESH]|Stress, Physiological[MESH]|Superoxides/metabolism[MESH]|Thapsigargin/pharmacology[MESH]|Time Factors[MESH]|Transcription Factor CHOP/*deficiency/genetics[MESH]|Transcription Factors/genetics/metabolism[MESH] |