A decrease of ATP production steered by PEDF in cardiomyocytes with oxygen-glucose deprivation is associated with an AMPK-dependent degradation pathway. (15th April 2018)

• Record Type: Journal Article
• Authors: Qiu, Fan; Zhang, Hao; Yuan, Yanliang; Liu, Zhiwei; Huang, Bing; Miao, Haoran; Liu, Xiucheng; Zhao, Qixiang; Zhang, Hu; Dong, Hongyan; Zhang, Zhongming
• Is Part Of: International journal of cardiology. Volume 257(2018)
• Page Start: 262
• Page End: 271
• Publication Date: 2018-04-15
• Subjects: Pigment epithelium derived factor -- AMP activated protein kinase -- Ubiquitination -- ATP production; Cardiology -- Periodicals; Electronic journals; 616.12
• DOI: 10.1016/j.ijcard.2018.01.034
• Languages: English
• ISSNs: 0167-5273

Abstract

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. Highlights: PEDF induces a decrease of ATP levels to maintain OGD cardiomyocyte viability. PEDF downregulates AMPK to reduce ATP production. AMPK inhibition fails to decrease ATP expenditure and was therefore detrimental. PPARγ binds to AMPKα to induce its ubiquitination and degradation.