GSKIP protects cardiomyocytes from hypoxia/reoxygenation-induced injury by enhancing Nrf2 activation via GSK-3β inhibition.

Li Yan, Gong Cheng, Guang Yang

Biochemical and biophysical research communications 2020 Oct 29

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Glycogen synthase kinase (GSK)-3β interaction protein (GSKIP), a key regulator of signaling transduction, is implicated in multiple pathological processes. However, whether GSKIP is involved in myocardial infarction is unknown. The present study was designed to determine the potential involvement of GSKIP in myocardial hypoxia/reoxygenation (H/R) injury, as an in vitro model for the study of myocardial infarction. Our data showed that H/R treatment triggered a marked decrease in GSKIP expression in cardiomyocytes. The upregulation of GSKIP significantly rescued the decreased viability of H/R-exposed cardiomyocytes and attenuated H/R-induced apoptosis and reactive oxygen species (ROS) generation. On the contrary, the depletion of GSKIP enhanced the sensitivity of cardiomyocytes to H/R-induced injury. Further data exhibited that GSKIP overexpression upregulated the nuclear expression of nuclear factor-erythroid-derived 2-related factor 2 (Nrf2) and increased Nrf2/antioxidant response element (ARE)-mediated transcription activity associated with upregulation of GSK-3β phosphorylation. Interestingly, inhibition of GSK-3β by a chemical inhibitor markedly enhanced Nrf2/ARE activation and abrogated GSKIP depletion-exacerbated sensitivity to H/R-induced injury. In addition, Nrf2 inhibition markedly reversed GSKIP overexpression-induced cardioprotective effect against H/R injury. Overall, these results demonstrate that overexpression of GSKIP alleviates H/R-induced apoptosis and oxidative stress in cardiomyocytes by enhancing Nrf2/ARE antioxidant signaling via GSK-3β inhibition. Our study indicates a potential role of GSKIP in myocardial infarction and GSKIP may serve as a promising molecular target for cardioprotection. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Li Yan, Gong Cheng, Guang Yang. GSKIP protects cardiomyocytes from hypoxia/reoxygenation-induced injury by enhancing Nrf2 activation via GSK-3β inhibition. Biochemical and biophysical research communications. 2020 Oct 29;532(1):68-75