Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine

• Published in: American Journal of Physiology: Cell Physiology 2007-09, Vol.293 (3), p.H1636-H1645
• Main Authors: Mao, Weike, Fukuoka, Shuji, Iwai, Chikao, Liu, Jiahao, Sharma, Virendra K, Sheu, Shey-Shing, Fu, Michael, Liang, Chang-seng
• Format: Article
• Language: English
• ISSN: 0363-6143; 1522-1563

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)-receptor-mediated 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 deoxytransferase-mediated dUTP nick-end labeling and caspase-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.