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Cardiomyocyte apopt...
Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine.
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Mao, Weike (author)
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Fukuoka, Shuji (author)
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Iwai, Chikao (author)
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Liu, Jiahao (author)
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Sharma, Virendra K (author)
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Sheu, Shey-Shing (author)
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- Fu, Michael, 1963 (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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Liang, Chang-seng (author)
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(creator_code:org_t)
- American Physiological Society, 2007
- 2007
- English.
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In: American journal of physiology. Heart and circulatory physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 293:3
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- 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)
Keyword
- 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
Publication and Content Type
- ref (subject category)
- art (subject category)
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