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Eur J Pharmacol. 2019 Jan 15;843:80-87. doi: 10.1016/j.ejphar.2018.11.016. Epub 2018 Nov 14.

Resveratrol protects cardiomyocytes against anoxia/reoxygenation via dephosphorylation of VDAC1 by Akt-GSK3 β pathway.

Author information

1
Jiangxi Provincial Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang 330006, PR China; Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330006, P.R. China.
2
Jiangxi University of Traditional Chinese Medicine, Nanchang 330000, PR China.
3
Jiangxi Provincial Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang 330006, PR China.
4
Department of Cardiac Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
5
Jiangxi Provincial Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang 330006, PR China. Electronic address: liaozp@ncu.edu.cn.

Abstract

Our previous studies showed that the effect of resveratrol preventing mitochondrial permeability transition pore (mPTP) opening in myocardial ischemia/reperfusion injury was achieved by regulating voltage-dependent anion channel 1 (VDAC1). However, the underlying mechanism remains unclear. Previous studies demonstrated that the activity and function of VDAC1 are highly regulated by post-translational modification. In present study, we investigated whether resveratrol modulates VDAC1 phosphorylation to achieve cardioprotection and explored the signaling pathways involved. Our findings demonstrated that anoxia/reoxygenation (A/R) treatment, an ischemia/reperfusion model in vitro, enhanced VDAC1 phosphorylation in cardiomyocytes. Moreover, we found phosphorylated VDAC1 showed increased affinity to Bax, whereas interaction with hexokinase 2 (HK2) was reduced. Accordingly, the generation of reactive oxygen species increased, the mitochondrial membrane potential collapsed, mPTP opening increased and cytochrome c released into cytoplasm, thereby leading to increased apoptosis. Moreover, our data showed that pretreatment with resveratrol prior to A/R injury inhibited VDAC1 phosphorylation. Dephosphorylated VDAC1 using pretreated resveratrol promoted dissociation with Bax and binding to HK2, which subsequently protected cardiomyocytes against A/R injury. In addition, Akt and its downstream glycogen synthase kinase 3 β (GSK3β) were phosphorylated by the action of resveratrol. Akt inhibitor IV abrogated Akt-GSK3β phosphorylation and thereby abolished the dephosphorylation activity of resveratrol on VDAC1. Moreover, all resveratrol-mediated protective effects on A/R injured cardiomyocytes were abolished by Akt inhibitor IV. Taken together, our data indicated that A/R injury enhanced VDAC1 phosphorylation in cardiomyocytes, whereas pretreatment with resveratrol dephosphorylated VDAC1 through the Akt-GSK3β pathway, thereby protecting cardiomyocytes against A/R injury.

KEYWORDS:

Akt-GSK3β pathway; Anoxia/reoxygenation; Cardiomyocyte; Phosphorylation; Resveratrol; Voltage-dependent anion channel 1

PMID:
30445019
DOI:
10.1016/j.ejphar.2018.11.016
[Indexed for MEDLINE]

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