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

Abstract

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

• Myocyte apoptosis
• p38 MAP kinase
• caspase-12, Akt

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.