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Sodium orthovanadate suppresses palmitate-induced cardiomyocyte apoptosis by regulation of the JAK2/STAT3 signaling pathway

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Abstract

Elevated circulatory free fatty acids (FFAs) especially saturated FFAs, such as palmitate (PA), are detrimental to the heart. However, mechanisms responsible for this phenomenon remain unknown. Here, the role of JAK2/STAT3 in PA-induced cytotoxicity was investigated in cardiomyocytes. We demonstrate that PA suppressed the JAK2/STAT3 pathway by dephosphorylation of JAK2 (Y1007/1008) and STAT3 (Y705), and thus blocked the translocation of STAT3 into the nucleus. Conversely, phosphorylation of S727, another phosphorylated site of STAT3, was increased in response to PA treatment. Pretreatment of JNK inhibitor, but not p38 MAPK inhibitor, inhibited STAT3 (S727) activation induced by PA and rescued the phosphorylation of STAT3 (Y705). The data suggested that JNK may be another upstream factor regulating STAT3, and verified the important function of P-STAT3 (Y705) in PA-induced cardiomyocyte apoptosis. Sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor, obviously inhibited PA-induced apoptosis by restoring JAK2/STAT3 pathways. This effect was diminished by STAT3 inhibitor Stattic. Collectively, our data suggested a novel mechanism that the inhibition of JAK2/STAT3 activation was responsible for palmitic lipotoxicity and SOV may act as a potential therapeutic agent by targeting JAK2/STAT3 in lipotoxic cardiomyopathy treatment.

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Abbreviations

PA:

Palmitate

FFAs:

Free fatty acids

BSA:

Bovine serum albumin

JAK:

Janus kinase

STAT3:

Signal transducer and activator of transcription 3

SOV:

Sodium orthovanadate

PTP:

Protein tyrosine phosphatase

PBS:

Phosphate buffered saline

NRVM:

Neonatal rat ventricular myocytes

ROS:

Reactive oxygen species

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Acknowledgments

This work was supported in part by The National 973 Research Project (No. 2014CB542400) and National Natural Science Foundation of China (Nos. 81570454 and 31371158).

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Authors and Affiliations

  1. Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, 250100, People’s Republic of China

    Jing Liu, Hui Fu, Fen Chang, Jinlan Wang, Shangli Zhang & Jing Zhao

  2. School of Pharmacy, Central South University, Changsha, 410023, People’s Republic of China

    Deling Yin

  3. Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA

    Yi Caudle & Deling Yin

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  1. Jing Liu
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Correspondence to Jing Zhao or Deling Yin.

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Liu, J., Fu, H., Chang, F. et al. Sodium orthovanadate suppresses palmitate-induced cardiomyocyte apoptosis by regulation of the JAK2/STAT3 signaling pathway. Apoptosis 21, 546–557 (2016). https://doi.org/10.1007/s10495-016-1231-8

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