title: Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine.
abstract: Evidence suggests that the autoimmune cardiomyopathy produced by a peptide corresponding to the sequence of the second extracellular loop of the beta(1)-adrenergic receptor (beta(1)-EC(II)) is mediated via a biologically active anti-beta(1)-EC(II) antibody, but the mechanism linking the antibody to myocyte apoptosis and cardiac dysfunction has not been well elucidated. Since the beta(1)-EC(II) autoantibody is a partial beta(1)-agonist, we speculate that the cardiomyopathy is produced by the beta(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(1)-EC(II) immunization, sham immunization, NE pellet, or beta(1)-EC(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(1)-EC(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(1)-EC(II) antibody in cultured neonatal cardiomyocytes. Thus ER stress occurs in autoimmune cardiomyopathy induced by beta(1)-EC(II) peptide, and this is enhanced by increased NE and caused by activation of the beta(1)-adrenergic receptor-coupled CaMKII, p38 MAPK, and ATF6 pathway.
authors.affiliation: University of Rochester Medical Center, Department of Medicine, Cardiology Division, Box 679, 601 Elmwood Ave., Rochester, NY 14642, USA.
authors.forename: Weike
authors.initials: W
authors.lastname: Mao
authors.forename: Shuji
authors.initials: S
authors.lastname: Fukuoka
authors.forename: Chikao
authors.initials: C
authors.lastname: Iwai
authors.forename: Jiahao
authors.initials: J
authors.lastname: Liu
authors.forename: Virendra K
authors.initials: VK
authors.lastname: Sharma
authors.forename: Shey-Shing
authors.initials: SS
authors.lastname: Sheu
authors.forename: Michael
authors.initials: M
authors.lastname: Fu
authors.forename: Chang-seng
authors.initials: CS
authors.lastname: Liang
mesh_terms: D051702:Activating Transcription Factor 6 / Q000502:physiology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001327:Autoimmune Diseases / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007074:Immunoglobulin G / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology*; D011817:Rabbits; D011897:Random Allocation; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D051702:Activating Transcription Factor 6; D000316:Adrenergic alpha-Agonists; D007074:Immunoglobulin G; D018342:Receptors, Adrenergic, beta-1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D009638:Norepinephrine