Cholesterol oxidation products such as oxysterols are considered critical factors in the atherosclerotic plaque formation since they induce oxidative stress, inflammation and apoptotic cell death. 27-hydroxycholesterol (27-OH) is one of the most represented oxysterols in atherosclerotic lesions. We recently showed that relatively low concentrations of 27-OH generated a strong survival signaling through an early and transient increase of cellular ROS level, that enhanced MEK-ERK/PI3K-Akt phosphorylation, in turn responsible of a sustained quenching of ROS production. It remains to identify the link between ERK/Akt up-regulation and the consequent quenching effect on ROS intracellular level that efficiently and markedly delay the pro-apoptotic effect of the oxysterol. Here we report on the potent activation of Nrf2 redox-sensitive transcription factor by low micromolar amount of 27-OH added to U937 promonocytic cells. The 27-OH-exerted induction of Nrf2 and subsequently of the target genes, HO-1 and NQO-1, was proved to be: (i) dependent upon the activation of ERK and Akt pathways, (ii) directly responsible for the quenching of intracellular oxidative stress and by this way (iii) ultimately responsible for the observed oxysterol-induced pro-survival response.

Nrf2 antioxidant defense is involved in survival signaling elicited by 27-hydroxycholesterol in human promonocytic cells.

GAMBA, Paola Francesca;GARGIULO, Simona;TESTA, GABRIELLA;STAURENGHI, ERICA;LEONARDUZZI, Gabriella Marisa;POLI, Giuseppe;
2016

Abstract

Cholesterol oxidation products such as oxysterols are considered critical factors in the atherosclerotic plaque formation since they induce oxidative stress, inflammation and apoptotic cell death. 27-hydroxycholesterol (27-OH) is one of the most represented oxysterols in atherosclerotic lesions. We recently showed that relatively low concentrations of 27-OH generated a strong survival signaling through an early and transient increase of cellular ROS level, that enhanced MEK-ERK/PI3K-Akt phosphorylation, in turn responsible of a sustained quenching of ROS production. It remains to identify the link between ERK/Akt up-regulation and the consequent quenching effect on ROS intracellular level that efficiently and markedly delay the pro-apoptotic effect of the oxysterol. Here we report on the potent activation of Nrf2 redox-sensitive transcription factor by low micromolar amount of 27-OH added to U937 promonocytic cells. The 27-OH-exerted induction of Nrf2 and subsequently of the target genes, HO-1 and NQO-1, was proved to be: (i) dependent upon the activation of ERK and Akt pathways, (ii) directly responsible for the quenching of intracellular oxidative stress and by this way (iii) ultimately responsible for the observed oxysterol-induced pro-survival response.
FREE RADICAL BIOLOGY & MEDICINE
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27-Hydroxycholesterol; Nrf2; Oxysterols; ROS; Survival signaling
Vurusaner, B; Gamba, P; Gargiulo, S; Testa, G; Staurenghi, E; Leonarduzzi, G; Poli, G; Basaga, H.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1600907
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