Si Gao1, Hong Li2, Xiao-jun Feng2, Min Li2, Zhi-ping Liu2, Yi Cai3, Jing Lu2, Xiao-yang Huang2, Jiao-jiao Wang2, Qin Li2, Shao-rui Chen2, Jian-tao Ye4, Pei-qing Liu5. 1. Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, No. 132 East Wai-huan Road, Guangzhou 510006, Guangdong, PR China; School of Medicine, Guangxi University of Science and Technology, No. 257 Liu-shi Road, Liuzhou 545005, Guangxi, PR China. 2. Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, No. 132 East Wai-huan Road, Guangzhou 510006, Guangdong, PR China. 3. Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, No. 132 East Wai-huan Road, Guangzhou 510006, Guangdong, PR China; Guangzhou Research Institute of Snake Venom, Guangzhou Medical College, Guangzhou 510182, Guangdong, PR China. 4. Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, No. 132 East Wai-huan Road, Guangzhou 510006, Guangdong, PR China. Electronic address: yejt@mail.sysu.edu.cn. 5. Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, No. 132 East Wai-huan Road, Guangzhou 510006, Guangdong, PR China. Electronic address: liupq@mail.sysu.edu.cn.
Abstract
BACKGROUND: α-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 α-enolase in doxorubicin (Dox)-induced cardiomyopathy as well as the underlying mechanisms. EXPERIMENTAL APPROACHES: The expression of α-enolase was detected in rat hearts and primary cultured rat cardiomyocytes with or without Dox administration. An adenovirus carrying short-hairpin interfering RNA targeting α-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 α-enolase expression in primary cultured rat cardiomyocytes, we investigated the role of endogenous, wide type and catalytically inactive mutant α-enolase in cardiomyocyte apoptosis and ATP generation. Furthermore, the involvement of α-enolase in AMPK phosphorylation was also studied. KEY RESULTS: The mRNA and protein expression of cardiac α-enolase was significantly upregulated by Dox. Genetic silencing of α-enolase in rat hearts and cultured cardiomyocytes attenuated Dox-induced apoptosis and mitochondrial dysfunction. In contrast, overexpression of wide-type or catalytically inactive α-enolase in cardiomyocytes mimicked the detrimental role of Dox in inducing apoptosis and ATP reduction. AMPK dephosphorylation was further demonstrated to be involved in the proapoptotic and ATP-depriving effects of α-enolase. CONCLUSION: Our findings provided the evidence that α-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.
BACKGROUND: α-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 α-enolase in doxorubicin (Dox)-induced cardiomyopathy as well as the underlying mechanisms. EXPERIMENTAL APPROACHES: The expression of α-enolase was detected in rat hearts and primary cultured rat cardiomyocytes with or without Dox administration. An adenovirus carrying short-hairpin interfering RNA targeting α-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 α-enolase expression in primary cultured rat cardiomyocytes, we investigated the role of endogenous, wide type and catalytically inactive mutant α-enolase in cardiomyocyte apoptosis and ATP generation. Furthermore, the involvement of α-enolase in AMPK phosphorylation was also studied. KEY RESULTS: The mRNA and protein expression of cardiac α-enolase was significantly upregulated by Dox. Genetic silencing of α-enolase in rat hearts and cultured cardiomyocytes attenuated Dox-induced apoptosis and mitochondrial dysfunction. In contrast, overexpression of wide-type or catalytically inactive α-enolase in cardiomyocytes mimicked the detrimental role of Dox in inducing apoptosis and ATP reduction. AMPK dephosphorylation was further demonstrated to be involved in the proapoptotic and ATP-depriving effects of α-enolase. CONCLUSION: Our findings provided the evidence that α-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.
Authors: Srinivas Ayyadevara; Meenakshisundaram Balasubramaniam; Samuel Kakraba; Ramani Alla; Jawahar L Mehta; Robert J Shmookler Reis Journal: Antioxid Redox Signal Date: 2017-06-28 Impact factor: 8.401
Authors: Menglin Liu; Menglong Wang; Jianfang Liu; Zhen Luo; Lei Shi; Ying Feng; Li Li; Lin Xu; Jun Wan Journal: Exp Ther Med Date: 2016-10-11 Impact factor: 2.447