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    • The Kelch like ECH associated protein Keap Nrf

    2022-12-01

    The Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 signaling pathway functions as one of the key regulator of the cellular defense system against oxidative stress [26]. Nrf2 is a redox-sensitive transcription factor, that is sequestered in the cytoplam by binding to Keap1; however, under oxidative stress, Nrf2 dissociates from Keap1 and translocates into the nucleus where it binds to antioxidant response element (ARE) sequences, codifying for antioxidant enzymes [27], [28]. A growing body of evidence has demonstrated the interplay between the Keap1/Nrf2 system and selective autophagy mainly relied on the p62/SQSTM1 protein (hereafter referred to as p62), which is an autophagy substrate and also a receptor for degradation of ubiquitinated protein aggregates, in turn associating with both LC3 and ubiquitin [29], [30]. Evidence suggests that p62 interacts with the Nrf2-binding site of Keap1 and competes with Nrf2 for the interaction with Keap1 which results in transcriptional activation of Nrf2 and its target gene expression [30], [31]. Moreover, Nrf2 regulates p62 expression by binding directly to ARE binding motif of the p62 promoter, suggesting a positive feedback loop between these two proteins [32]. To investigate in depth the molecular mechanism of Nrf2-modulated 27-OH induced survival signaling [19], [20], in the present paper we aimed to elucidate the potential stimulation of pro-survival autophagy by low micromolar concentration of 27-OH and to explore the relevance between Nrf2 pathway and selective autophagy, with regard to the modulation of p62 protein. The obtained data showed that 27-OH up-regulated autophagic proteins including LC3 and Beclin 1 in a ROS-dependent manner in human promonocytic cells. Indeed, autophagy seems involved in 27-OH-induced Nrf2 modulated survival signaling.
    Materials and methods
    Results
    Discussion Oxysterols are quantitatively relevant components of oxidized low density lipoproteins (oxLDLs) and their multifaceted biochemical properties were well-characterized in vascular Quinidine [2], [3], [17]. 27-OH is one of the most represented oxysterols in the human circulation and also in atherosclerotic lesions [43]. On behalf of its important role in pathophysiology, 27-OH has been established as a good ligand of nuclear receptors that leads to modulate cell viability, immunological response and metabolism [7], [8]. In this relation, eliciting survival and functional signals, modulated by 27-OH, might contribute to expand the knowledge about the molecular mechanisms of the pathogenesis of several oxysterol-related diseases. Autophagy is a dynamic process in which long lived proteins and cellular organelles are removed by autophagosomes. It has become accepted that although autophagy has been regarded as cell survival mechanism, under certain conditions, excessive autophagy may lead to a non-apoptotic type of cell death [22]. Despite the increasing interest in understanding the mechanism of autophagy, there is limited information on how cellular signaling pathways regulate this complex process. It is now well established that autophagy is stimulated in advanced atherosclerotic plaques by inflammation and oxidized lipids where progression of atherosclerosis is characterized by formation of these plaques [44]. The protective role of autophagy in atherosclerosis involves the removal of damaged organelles by autophagy in response to mild oxidative stress which contributes to cellular recovery [45]. While the effects of autophagy on pathological processes including atherosclerosis are complex, further studies are required to distinguish the relation between oxysterols and autophagy. In the current study, we examined the mechanism by which 27-OH induces autophagy using U937 promonocytic cells. We demonstrated that the ROS-mediated induction of autophagy by low micromolar concentration of 27-OH is primary responsible for the observed oxysterol-induced pro-survival response and stimulated expression of antioxidant Nrf2. Moreover, the critical role of Nrf2 in controlling autophagy via p62 in response to oxidative stress was observed. To the best of our knowledge, this is the first demonstration of the stimulation of pro-survival autophagy by 27-OH at low micromolar concentrations in promonocytic cells. In consistent with our findings, Martinet et al. showed that 7-ketocholesterol (7-K) stimulated autophagy in human vascular smooth muscle cells (SMCs) in terms of myelin figure formation, LC3 processing and also intense protein ubiquitination [24]. In contrast, in another study using SMCs, high concentrations of 7-K treatment caused autophagic cell death via autophagic vesicle formation with LC3 processing. This autophagic response induced by 7-K Quinidine attenuated SMC apoptosis induced by low concentrations of lipophilic statins by suppressing caspase activation [46]. This different outcome of the autophagic response may be due to the relatively greater cytotoxicity of 7-K than 27-OH.