Figure 3.

Role of HNE on Nrf2-mediated anti-oxidative signaling: Nrf2 is a master regulator of various anti-oxidative and anti-inflammatory pathways in the cells. Under basal conditions, Nrf2 is bound to KEAP-1 and remains inactive. KEAP-1 is an adaptor protein and association of KEAP-1 with Cul3, promotes proteasomal degradation of the Nrf2-KEAP1 complex. However, when activated by an external stimulus, (a) phosphorylation and dissociation of Nrf2 occurs from the Nrf2-Keap1 complex leading to nuclear translocation of Nrf2 and transcription of target genes. (b) HNE could promote Nrf2 activation either by modifying the C151 residues in KEAP-1 or by promoting Nrf2 phosphorylation directly. Apart from directly affecting Nrf2 and KEAP-1, various upstream kinases such as p38MAPK, PKC and ERK can also be modulated by HNE, which further initiates the activation of Nrf2.