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

Antagonizing TNF-α signaling attenuates chronic inflammatory disease, but is associated with adverse effects on the cardiovascular system. Therefore the impact of TNF-α on basal control of redox signaling events needs to be understand in more depth. This is particularly important for the Keap1/Nrf2...

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Detalles Bibliográficos
Autores principales: Shanmugam, Gobinath, Narasimhan, Madhusudhanan, Sakthivel, Ramasamy, Kumar R, Rajesh, Davidson, Christopher, Palaniappan, Sethu, Claycomb, William W., Hoidal, John R., Darley-Usmar, Victor M., Rajasekaran, Namakkal Soorappan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961303/
https://www.ncbi.nlm.nih.gov/pubmed/27423013
http://dx.doi.org/10.1016/j.redox.2016.06.004
Descripción
Sumario:Antagonizing TNF-α signaling attenuates chronic inflammatory disease, but is associated with adverse effects on the cardiovascular system. Therefore the impact of TNF-α 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-α signaling attenuates the TNF-α dependent activation of this cytoprotective pathway. HL-1 cardiomyocytes and TNF receptor1/2 (TNFR1/2) double knockout mice (DKO) were used as experimental models. TNF-α (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-α (>10–50 ng/ml) were markedly suppressive of the Keap1/Nrf2 response and associated with cardiomyocyte death marked by an increase in cleavage of caspase-3 and PARP. In vivo experiments with TNFR1/2-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-α 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.