Pro-apoptotic effects of anti-beta1-adrenergic receptor antibodies in cultured rat cardiomyocytes: actions on endoplasmic reticulum and the prosurvival PI3K-Akt pathway.
An anti-beta(1)-adrenergic receptor antibody against the second extracellular receptor loop (beta(1)-EC(II)) has been shown to cause myocyte apoptosis and dilated cardiomyopathy in animals. We report in this review that the anti-beta(1)-EC(II) antibody increases intracellular Ca(++) transients and exerts a direct apoptotic effect in cultured neonatal rat cardiomyocytes. Both Fab and Fc fragments are required for the full expression of the apoptotic effects of the anti-beta(1)-EC(II) antibody. Our studies further suggest that the anti-beta(1)-EC(II)-antibody acts primarily on the cardiac beta(1)-adrenergic receptor and its post-receptor activation of Ca(++)/Calmodulin dependent protein kinase II (CaMKII) and p-38 mitogen-activated protein kinase (MAPK), leading to endoplasmic reticulum stress as evidenced by the increased expressions of GRP78 and CHOP, as well as the increased processing of the initiator procaspase-12. Also, observed with the apoptotic effect of anti-beta(1)-EC(II) antibody is reduced activity of the phosphatidylinositol (PI) 3-kinase/Akt/STAT3 signaling pathway. Our results suggest that agents that block the activation of p38-MAPK/endoplasmic reticulum stress or reverse the suppression of the prosurvival PI3K/Akt/STAT3 pathway may be explored as potential novel therapeutic modalities in the treatment of dilated cardiomyopathy.
Liang
Chang-Seng
CS
Department of Medicine, Cardiology Division, University of Rochester Medical Center, Rochester, NY 14642, USA.
Mao
Weike
W
Liu
Jiahao
J
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D009202:Cardiomyopathies / Q000276:immunology / Q000378:metabolism; D053454:Caspase 12 / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000276:immunology*; D015398:Signal Transduction
D000906:Antibodies; D007074:Immunoglobulin G; D018342:Receptors, Adrenergic, beta-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053454:Caspase 12