부산대학교 도서관

Evidence suggests that the autoimmune cardiomyopathy produced by a peptide corresponding to the sequence of the second extracellular loop of the [[beta].sub.1]-adrenergic receptor ([[beta].sub.1]-[EC.sub.II]) is mediated via a biologically active anti-[[beta].sub.1]-[EC.sub.II] antibody, but the mechanism linking the antibody to myocyte apoptosis and cardiac dysfunction has not been well elucidated. Since the [[beta].sub.1]-[EC.sub.II] autoantibody is a partial [[beta].sub.1]-agonist, we speculate that the cardiomyopathy is produced by the [[beta].sub.1]-receptormediated stimulation of the CaMKII-p38 MAPK-ATF6 signaling pathway and endoplasmic reticulum (ER) stress, and that excess norepinephrine (NE) exaggerates the cardiomyopathy. Rabbits were randomized to receive [[beta].sub.1]-[EC.sub.II] immunization, sham immunization, NE pellet, or [[beta].sub.1]-[EC.sub.II] immunization plus NE pellet for 6 mo. Heart function was measured by echocardiography and catheterization. Myocyte apoptosis was determined by terminal deoxytransferasemediated dUTP nick-end labeling and easpase-3 activity, whereas CaMKII, MAPK family (JNK, p38, ERK), and ER stress signals (ATF6, GRP78, CHOP, caspase-12) were measured by Western blot, immunohistochemistry, and kinase activity assay. [[beta].sub.1]-[EC.sub.II] immunization produced progressive LV dilation, systolic dysfunction, and myocyte apoptosis. These changes were associated with activation of GRP78 and CHOP and increased cleavage of caspase-12, as well as increased CaMKII activity, increased phosphorylation of p38 MAPK, and nucleus translocation of cleaved ATF6. NE pellet produced additive effects. In addition, KN-93 and SB 203580 abolished the induction of ER stress and cell apoptosis produced by the [[beta].sub.1]-[EC.sub.II] antibody in cultured neonatal cardiomyocytes. Thus ER stress occurs in autoimmune cardiomyopathy induced by [[beta].sub.1]-[EC.sub.II] peptide, and this is enhanced by increased NE and caused by activation of the [[beta].sub.1]-adrenergic receptor-coupled CaMKII, p38 MAPK, and ATF6 pathway. cardiomyocytes; signal transduction