Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic-Ischemic Brain Damage in Neonatal Rats

Deyuan Li; Xihong Li; Jinlin Wu; Jinhui Li; Li Zhang; Tao Xiong; Jun Tang; Yi Qu; Dezhi Mu

doi:10.1371/journal.pone.0132998

Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic-Ischemic Brain Damage in Neonatal Rats

PLoS One. 2015 Jul 14;10(7):e0132998. doi: 10.1371/journal.pone.0132998. eCollection 2015.

Authors

Deyuan Li¹, Xihong Li¹, Jinlin Wu¹, Jinhui Li¹, Li Zhang¹, Tao Xiong¹, Jun Tang¹, Yi Qu¹, Dezhi Mu²

Affiliations

¹ Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, Sichuan 610041, PR China.
² Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, Sichuan 610041, PR China; Department of Neurology, University of California San Francisco, San Francisco, CA 94143, United States of America.

Abstract

c-Jun N-terminal kinase (JNK) plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after hypoxia-ischemia (HI). In this study, we generated an HI model using postnatal day 7 rats. Fluorescence immunolabeling and Western blot assays were used to detect the distribution and expression of total and phosphorylated JNK and FOXO3a and the pro-apoptotic proteins Bim and CC3. We found that JNK phosphorylation was accompanied by FOXO3a dephosphorylation, which induced FOXO3a translocation into the nucleus, resulting in the upregulation of levels of Bim and CC3 proteins. Furthermore, we found that JNK inhibition by AS601245, a specific JNK inhibitor, significantly increased FOXO3a phosphorylation, which attenuated FOXO3a translocation into the nucleus after HI. Moreover, JNK inhibition downregulated levels of Bim and CC3 proteins, attenuated neuronal apoptosis and reduced brain infarct volume in the developing rat brain. Our findings suggest that the JNK/FOXO3a/Bim pathway is involved in neuronal apoptosis in the developing rat brain after HI. Agents targeting JNK may offer promise for rescuing neurons from HI-induced damage.

Publication types

Research Support, Non-U.S. Gov't
Retracted Publication

MeSH terms

Acetonitriles / pharmacology
Active Transport, Cell Nucleus / drug effects
Animals
Animals, Newborn
Apoptosis Regulatory Proteins / metabolism*
Apoptosis* / drug effects
Bcl-2-Like Protein 11
Benzothiazoles / pharmacology
Brain / drug effects
Brain / metabolism
Brain / pathology
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Female
Forkhead Box Protein O3
Forkhead Transcription Factors / metabolism*
Gene Expression Regulation, Enzymologic / drug effects
Hypoxia-Ischemia, Brain / metabolism
Hypoxia-Ischemia, Brain / pathology*
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases / metabolism*
MAP Kinase Signaling System* / drug effects
Male
Membrane Proteins / metabolism*
Neurons / drug effects
Neurons / metabolism
Neurons / pathology*
Phosphoproteins / metabolism
Phosphorylation / drug effects
Proto-Oncogene Proteins / metabolism*
Rats
Rats, Sprague-Dawley
Up-Regulation / drug effects

Substances

1,3-benzothiazol-2-yl(2-((2-(3-pyridinyl)ethyl)amino)-4-pyrimidinyl)acetonitrile
Acetonitriles
Apoptosis Regulatory Proteins
Bcl-2-Like Protein 11
Bcl2l11 protein, rat
Benzothiazoles
FOXO3 protein, rat
Forkhead Box Protein O3
Forkhead Transcription Factors
Membrane Proteins
Phosphoproteins
Proto-Oncogene Proteins
JNK Mitogen-Activated Protein Kinases

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81000262 to Deyuan Li, No. 81330016 and 31171020 to Dezhi Mu; No. 81172174 and 81270724 to Yi Qu, No. 81100457 to Jinhui Li, and No. 81200462 to Li Zhang), the Major State Basic Research Development Program (2013CB967404), grants from the Ministry of Education of China (313037, 20110181130002), a grant from the State Commission of Science Technology of China (2012BAI04B04), grants from the Science and Technology Bureau of Sichuan province (2010SZ0280, 2011JTD0005, 2012SZ0150), and the Grant of Clinical Discipline Program (Neonatology) from the Ministry of Health of China (1311200003303).