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14,15-EET Suppresses Neuronal Apoptosis in Ischemia–Reperfusion Through the Mitochondrial Pathway

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Abstract

Neuronal apoptosis mediated by the mitochondrial apoptosis pathway is an important pathological process in cerebral ischemia–reperfusion injury. 14,15-EET, an intermediate metabolite of arachidonic acid, can promote cell survival during ischemia/reperfusion. However, whether the mitochondrial apoptotic pathway is involved this survival mechanism is not fully understood. In this study, we observed that infarct size in ischemia–reperfusion injury was reduced in sEH gene knockout mice. In addition, Caspase 3 activation, cytochrome C release and AIF nuclear translocation were also inhibited. In this study, 14,15-EET pretreatment reduced neuronal apoptosis in the oxygen–glucose deprivation and re-oxygenation group in vitro. The mitochondrial apoptosis pathway was also inhibited, as evidenced by AIF translocation from the mitochondria to nucleus and the reduction in the expressions of cleaved-caspase 3 and cytochrome C in the cytoplasm. 14,15-EET could reduce neuronal apoptosis through upregulation of the ratio of Bcl-2 (anti-apoptotic protein) to Bax (apoptosis protein) and inhibition of Bax aggregation onto mitochondria. PI3K/AKT pathway is also probably involved in the reduction of neuronal apoptosis by EET. Our study suggests that 14,15-EET could suppress neuronal apoptosis and reduce infarct volume through the mitochondrial apoptotic pathway. Furthermore, the PI3K/AKT pathway also appears to be involved in the neuroprotection against ischemia–reperfusion by 14,15-EET.

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Abbreviations

14,15-EET:

14,15-Epoxyeicosatrienoic acid

OGD/R:

Oxygen–glucose deprivation and reoxygenation

sEH:

Soluble epoxide hydrolase

AIF:

Apoptosis-inducing factor

MCAO:

Middle cerebral artery occlusion

CREB:

cAMP response element-binding protein

LDH:

Lactate dehydrogenase

Smac:

Second mitochondrial activator of caspases

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Acknowledgements

This work was supported by Henan Province Research Program of Basic and Advanced Technology (162300410102), Henan Postdoctoral Foundation (2015051) and Henan Province Foundation for University Key Teacher (15A180031, 16A330001).

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Authors and Affiliations

  1. School of Nursing and Health Sciences, Henan University, Kaifeng, 475004, Henan, People’s Republic of China

    Hui-Xia Geng & Li Zhang

  2. Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004, Henan, People’s Republic of China

    Rui-Ping Li, Ying-Ge Li, Xiao-Qing Wang, Jin-Bo Deng, Lai Wang & Jie-Xin Deng

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  1. Hui-Xia Geng
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Correspondence to Lai Wang or Jie-Xin Deng.

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Geng, HX., Li, RP., Li, YG. et al. 14,15-EET Suppresses Neuronal Apoptosis in Ischemia–Reperfusion Through the Mitochondrial Pathway. Neurochem Res 42, 2841–2849 (2017). https://doi.org/10.1007/s11064-017-2297-6

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  • DOI: https://doi.org/10.1007/s11064-017-2297-6

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