A biphasic effect of TNF-alpha in regulation of the Keap1/Nrf2 pathway in cardiomyocytes

作者：Shanmugam Gobinath; Narasimhan Madhusudhanan; Sakthivel Ramasamy; Kumar Rajesh R; Davidson Christopher; Palaniappan Sethu; Claycomb William W; Hoidal John R; Darley Usmar Victor M; Rajasekaran Namakkal Soorappan^*

来源：Redox Biology, 2016, 9: 77-89.

DOI：10.1016/j.redox.2016.06.004

• Nrf2 signaling
• TNF-alpha
• Antioxidants
• Oxidative stress
• Apoptosis

Antagonizing TNF-alpha signaling attenuates chronic inflammatory disease, but is associated with adverse effects on the cardiovascular system. Therefore the impact of TNF-alpha on basal control of redox signaling events needs to be understand in more depth. This is particularly important for the Keap1/Nrf2 pathway in the heart and in the present study we hypothesized that inhibition of a low level of TNF-alpha signaling attenuates the TNF-alpha dependent activation of this cytoprotective pathway. HL-1 cardiomyocytes and TNF receptor1/2 (TNER1/2) double knockout mice (DKO) were used as experimental models. TNF-alpha (2-5 ng/ ml, for 2 h) evoked significant nuclear translocation of Nrf2 with increased DNA/promoter binding and transactivation of Nrf2 targets. Additionally, this was associated with a 1.5 fold increase in intracellular glutathione (GSH). Higher concentrations of TNF-alpha (> 10-50 ng/ml) were markedly suppressive of the Keapl/Nrf2 response and associated with cardiomyocyte death marked by an increase in cleavage of caspase-3 and PARP. In vivo experiments with TNER1/2-DKO demonstrates that the expression of Nrf2 regulated proteins (NQO1, HO-1, G6PD) were significantly downregulated in hearts of the DKO when compared to WT mice indicating a weakened antioxidant system under basal conditions. Overall, these results indicate that TNF-alpha exposure has a bimodal effect on the Keap1/Nrf2 system and while an intense inflammatory activation suppresses expression of antioxidant proteins a low level appears to be protective.

• 出版日期2016-10