alpha-Enolase plays a catalytically independent role in doxorubicin-induced cardiomyocyte apoptosis and mitochondrial dysfunction

作者：Gao Si; Li Hong; Feng Xiao jun; Li Min; Liu Zhi ping; Cai Yi; Lu Jing; Huang Xiao yang; Wang Jiao jiao; Li Qin; Chen Shao rui; Ye Jian tao^*; Liu Pei qing

来源：Journal of Molecular and Cellular Cardiology, 2015, 79: 92-103.

DOI：10.1016/j.yjmcc.2014.11.007

• alpha-Enolase
• Cardiomyocyte
• Doxorubicin
• Apoptosis
• Mitochondria
• AMPK

Background: alpha-Enolase is a glycolytic enzyme with "second jobs" beyond its catalytic activity. However, its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the role of alpha-enolase in doxorubicin (Dox)-induced cardiomyopathy as well as the underlying mechanisms.
Experimental approaches: The expression of alpha-enolase was detected in rat hearts and primary cultured rat cardiomyocytes with or without Dox administration. An adenovirus carrying short-hairpin interfering RNA targeting alpha-enolase was constructed and transduced specifically into the heart by intramyocardial injection. Heart function, cell apoptosis and mitochondrial function were measured following Dox administration. In addition, by using gain-and loss-of-function approaches to regulate alpha-enolase expression in primary cultured rat cardiomyocytes, we investigated the role of endogenous, wide type and catalytically inactive mutant alpha-enolase in cardiomyocyte apoptosis and ATP generation. Furthermore, the involvement of alpha-enolase in AMPK phosphorylation was also studied.
Key results: The mRNA and protein expression of cardiac alpha-enolase was significantly upregulated by Dox. Genetic silencing of alpha-enolase in rat hearts and cultured cardiomyocytes attenuated Dox-induced apoptosis and mitochondrial dysfunction. In contrast, overexpression of wide-type or catalytically inactive a-enolase in cardiomyocytes mimicked the detrimental role of Dox in inducing apoptosis and ATP reduction. AMPK dephosphoiylation was further demonstrated to be involved in the proapoptotic and ATP-depriving effects of a-enolase.
Conclusion: Our findings provided the evidence that alpha-enolase has a catalytically independent role in inducing cardiomyocyte apoptosis and mitochondrial dysfunction, which could be at least partially contributed to the inhibition of AMPK phosphorylation.

• 单位
  广州医学院