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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/H1636    most recent 01377.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Mao, W. Articles by Liang, C.-s. Search for Related Content PubMed PubMed Citation Articles by Mao, W. Articles by Liang, C.-s.

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

Cardiology Division, Department of Medicine, and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York; and Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden

Submitted 18 December 2006 ; accepted in final form 29 May 2007

Evidence suggests that the autoimmune cardiomyopathy produced by a peptide corresponding to the sequence of the second extracellular loop of the ₁-adrenergic receptor (₁-EC_II) is mediated via a biologically active anti-₁-EC_II antibody, but the mechanism linking the antibody to myocyte apoptosis and cardiac dysfunction has not been well elucidated. Since the ₁-EC_II autoantibody is a partial ₁-agonist, we speculate that the cardiomyopathy is produced by the 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 ₁-EC_II immunization, sham immunization, NE pellet, or 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. 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 ₁-EC_II antibody in cultured neonatal cardiomyocytes. Thus ER stress occurs in autoimmune cardiomyopathy induced by ₁-EC_II peptide, and this is enhanced by increased NE and caused by activation of the ₁-adrenergic receptor-coupled CaMKII, p38 MAPK, and ATF6 pathway.

cardiomyocytes; signal transduction

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