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Original

Pro-apoptotic effects of anti-β1-adrenergic receptor antibodies in cultured rat cardiomyocytes: Actions on endoplasmic reticulum and the prosurvival PI3K-Akt pathway

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Pages 434-441 | Received 02 Feb 2008, Accepted 28 Feb 2008, Published online: 07 Jul 2009
 

Abstract

An anti-β1-adrenergic receptor antibody against the second extracellular receptor loop (β1-ECII) has been shown to cause myocyte apoptosis and dilated cardiomyopathy in animals. We report in this review that the anti-β1-ECII 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-β1-ECII antibody. Our studies further suggest that the anti-β1-ECII-antibody acts primarily on the cardiac β1-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-β1-ECII 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.

Acknowledgements

The studies were supported in part by National Heart, Lung, and Blood Grant HL-68151. The authors acknowledge the excellent technical support provided by Megan Simeone and Robin Stuart Buttles.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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