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A decrease of ATP production steered by PEDF in cardiomyocytes with oxygen-glucose deprivation is associated with an AMPK-dependent degradation pathway

Authors :
Hu Zhang
Zhiwei Liu
Fan Qiu
Qixiang Zhao
Haoran Miao
Yanliang Yuan
Xiucheng Liu
Hao Zhang
Zhongming Zhang
Bing Huang
Hongyan Dong
Source :
International Journal of Cardiology. 257:262-271
Publication Year :
2018
Publisher :
Elsevier BV, 2018.

Abstract

Aims The activated AMP activated protein kinase (AMPK) serves as a transient protective cardiovascular kinase via preserving adenosine triphosphate (ATP) production under ischemic conditions. However, recent studies reveal that inhibition of AMPK in stroke is neuroprotection. Pigment epithelium derived factor (PEDF) is also known for the protection of ischemic cardiomyocytes. However, the relationship between PEDF and AMPK in cardiomyocytes is poorly understood. Methods and results Rat neonatal and adult left ventricular cardiomyocytes were isolated and subjected to oxygen-glucose deprivation (OGD). During OGD, PEDF significantly reduced AMPKα levels to decrease ATP production and reduced ATP expenditure both in neonatal and adult cardiomyocytes, which increased energy reserves and cell viability. Importantly, pharmacological AMPK inhibitor reduced ATP production but failed to decrease ATP expenditure, thus leading cells into death. Furthermore, AMPKα was degraded by a ubiquitin-dependent proteasomal degradation pathway, which is associated with a PEDF/PEDFR/peroxisome proliferator activated receptor γ (PPARγ) axis. Inhibition of PPARγ or proteasome disrupted the interaction of AMPKα and PPARγ, which abolished AMPKα degradation. Importantly, the decrease of AMPKα and ATP level was normalized after recovery of oxygen and glucose. Conclusions We demonstrate a novel mechanism for regulation of cardiac ATP production by PEDF involving AMPKα and PPARγ. PEDF promotes proteasomal degradation of AMPK and, subsequently, reduces ATP production. The reduction of ATP production associated with the decrease of ATP expenditure completed by PEDF increase energy reserves and reduces cell energy failure, prolonging the cell activity during OGD.

Details

ISSN :
01675273
Volume :
257
Database :
OpenAIRE
Journal :
International Journal of Cardiology
Accession number :
edsair.doi.dedup.....ef014e42d2783f4108b36b67d954d931
Full Text :
https://doi.org/10.1016/j.ijcard.2018.01.034