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Molecular and Cellular Biology, November 2005, p. 9554-9575, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9554-9575.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

AMP-Activated Protein Kinase Protects Cardiomyocytes against Hypoxic Injury through Attenuation of Endoplasmic Reticulum Stress

Kazuo Terai,1 Yoshimune Hiramoto,1 Mitsuru Masaki,1 Shoko Sugiyama,1 Tadashi Kuroda,1 Masatsugu Hori,1 Ichiro Kawase,2 and Hisao Hirota1*

Department of Cardiovascular Medicine,1 Respiratory Medicine and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan2

Received 6 June 2005/ Returned for modification 30 June 2005/ Accepted 16 August 2005

Oxygen deprivation leads to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), causing ER stress. Under conditions of ER stress, inhibition of protein synthesis and up-regulation of ER chaperone expression reduce the misfolded proteins in the ER. AMP-activated protein kinase (AMPK) is a key regulatory enzyme involved in energy homeostasis during hypoxia. It has been shown that AMPK activation is associated with inhibition of protein synthesis via phosphorylation of elongation factor 2 (eEF2) in cardiomyocytes. We therefore examined whether AMPK attenuates hypoxia-induced ER stress in neonatal rat cardiomyocytes. We found that hypoxia induced ER stress, as assessed by the expression of CHOP and BiP and cleavage of caspase 12. Knockdown of CHOP or caspase 12 through small interfering RNA (siRNA) resulted in decreased expression of cleaved poly(ADP-ribose) polymerase following exposure to hypoxia. We also found that hypoxia-induced CHOP expression and cleavage of caspase 12 were significantly inhibited by pretreatment with 5-aminoimidazole-4-carboxyamide-1-ß-D-ribofuranoside (AICAR), a pharmacological activator of AMPK. In parallel, adenovirus expressing dominant-negative AMPK significantly attenuated the cardioprotective effects of AICAR. Knockdown of eEF2 phosphorylation using eEF2 kinase siRNA abolished these cardioprotective effects of AICAR. Taken together, these findings demonstrate that activation of AMPK contributes to protection of the heart against hypoxic injury through attenuation of ER stress and that attenuation of protein synthesis via eEF2 inactivation may be the mechanism of cardioprotection by AMPK.

* Corresponding author. Mailing address: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita City, Osaka 565-0871, Japan. Phone: 81-6-6879-3835. Fax: 81-6-6879-3839. E-mail: hirota{at}imed3.med.osaka-u.ac.jp.

Molecular and Cellular Biology, November 2005, p. 9554-9575, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9554-9575.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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