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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Microbiology in the medical area (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

Nyckelord

Activating Transcription Factor 6

physiology

Adrenergic alpha-Agonists

pharmacology

Animals

Apoptosis

physiology

Autoimmune Diseases

metabolism

pathology

physiopathology

Blood Pressure

drug effects

physiology

Ca(2+)-Calmodulin Dependent Protein Kinase

physiology

Cardiomyopathies

metabolism

pathology

physiopathology

Caspase 3

metabolism

Cells

Cultured

Endoplasmic Reticulum

physiology

Heart Rate

drug effects

physiology

Immunoglobulin G

pharmacology

Myocytes

Cardiac

metabolism

pathology

Norepinephrine

pharmacology

physiology

Rabbits

Random Allocation

Receptors

Adrenergic

beta-1

physiology

Signal Transduction

drug effects

physiology

p38 Mitogen-Activated Protein Kinases

physiology

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