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Isoproterenol instigates cardiomyocyte apoptosis and heart failure via AMPK inactivation-mediated endoplasmic reticulum stress

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Abstract

A prolonged or excessive adrenergic activation leads to myocyte loss and heart dysfunction; however, how it contributes to heart failure remains poorly defined. Here we show that isoproterenol (ISO) induced aberrant endoplasmic reticulum (ER) stress and apoptotic cell death, which was inhibited by activating the AMP-activated protein kinase (AMPK) in vitro and in vivo. Persistent ISO stimulation suppressed the AMPK phosphorylation and function, resulting in enhanced ER stress and the subsequent cell apoptosis in cardiomyocytes in vitro and in vivo. AMPK activation decreased the aberrant ER stress, apoptosis, and brain natriuretic peptide (BNP) release in ISO-treated cardiomyocytes, which was blocked by AMPK inhibitor Compound C. Importantly, increased ER stress and apoptosis were observed in ISO-treated cardiomyocytes isolated from AMPKα2−/− mice. Inhibition of ER stress attenuated the apoptosis but failed to reverse AMPK inhibition in ISO-treated cardiomyocytes. Moreover, metformin administration activated AMPK and reduced both ER stress and apoptosis in ISO-induced rat heart failure in vivo. We conclude that ISO, via AMPK inactivation, causes aberrant ER stress, cardiomyocyte injury, BNP release, apoptosis, and hence heart failure in vivo, all of which are inhibited by AMPK activation.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

AMPK:

Adenosine monophosphate-activated protein kinase

ATF:

Activating transcription factor

BNP:

B-type natriuretic peptide

CHOP:

C/EBP homologous protein

ER:

Endoplasmic reticulum

GRP:

Glucose-regulated protein

IRE:

Inositol-requiring enzyme-1α

ISO:

Isoproterenol

PERK:

Protein kinase R-like ER kinase

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Acknowledgments

This study was supported in part by the National Natural Science Foundation of China (81000063 to Ma AQ), Scientist Development Grant from American Heart Association (11SDG5560036 to Song P), and Oklahoma Center for the Advancement of Science and Technology (HR12-061 to Song P). The AMPKα2−/− mice were kindly provided by Dr. Benoit Viollet from Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, First Affiliated Hospital of Medical College, School of Medicine, Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China

    Xiao-Zhen Zhuo, Yue Wu, Ya-Juan Ni, Jun-Hui Liu, Min Gong, Xue-Hui Wang, Feng Wei, Ting-Zhong Wang, Zuyi Yuan & Ai-Qun Ma

  2. Section of Molecular Medicine, Department of Internal Medicine, University of Oklahoma Health Sciences Center, 941 Stanton L Young Blvd, Oklahoma City, OK, 73104, USA

    Yue Wu & Ping Song

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  1. Xiao-Zhen Zhuo
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  10. Ai-Qun Ma
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Corresponding authors

Correspondence to Ai-Qun Ma or Ping Song.

Additional information

Zhuo X Z and Wu Y contributed equally to this study.

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Zhuo, XZ., Wu, Y., Ni, YJ. et al. Isoproterenol instigates cardiomyocyte apoptosis and heart failure via AMPK inactivation-mediated endoplasmic reticulum stress. Apoptosis 18, 800–810 (2013). https://doi.org/10.1007/s10495-013-0843-5

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