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  • Heme activates the master regulator of the anti oxidant

    2022-01-17

    Heme activates the master regulator of the anti-oxidant stress response, NRF2, which mediates the up-regulation of a battery of phase II detoxifying genes [106]. Remarkably, HO-1 induction by NRF2 is regulated via an interplay with the transcriptional repressor BACH1 at the Maf recognition K-Ras(G12C) inhibitor 12 synthesis (MARE) in the HO-1 promoter. Heme binds to cysteine-proline motifs of BACH1, which then leads to its nuclear export and proteasomal degradation [107], [108]. In parallel, Nrf2 translocates into the nucleus and binds to the BACH1 free MARE to induce transcription. Notably, inactivation of BACH1 is sufficient to up-regulate HO-1 gene expression [109], [110], [111] and inactivation of BACH1 by heme also modulates expression of the iron-regulatory genes ferritin and ferroportin [112], [113]. Similarly, heme-protein complexes such as heme-Hx have been shown to induce HO-1 in macrophages via BACH1 regulation [114]. Potential mechanisms that control BACH1 inactivation by non-heme inducers of HO-1 are less well understood, but HO-1 inducers such as arsenite and cadmium have been shown to regulate the nuclear export of BACH1 [111], [115]. It is plausible that mechanisms of BACH1 export, which are independent of heme binding, are involved in this regulation [116], [117], [118]. In conclusion, HO-1 is specifically regulated via inactivation of the heme-dependent nuclear repressor BACH1. The potency of putative selective pharmacological HO-1 inducers may be tested for their ability to inactivate BACH1-mediated repression.
    Species-specific differences in HO-1 gene regulation Species-specific differences are known for the regulation of various TLR4-dependent inflammatory genes in mouse and human macrophages [119]. Similarly, inter-species differences also apply for the regulation of HO-1 in response to various stimuli such as heat-shock [120], interferon-γ [121], hypoxia [122] and LPS [123] in mouse and human, which may be critical for translating such experimental findings from mice into clinical applications. The complexity of HO-1 regulation has been further increased by cell-type-specific regulatory HO-1 gene expression patterns in humans [124], [125] Heme-mediated induction of HO-1 requires two binding sites in the distal promoters of the mouse and human genes, but the human promoter requires an additional enhancer element for the up-regulation of HO-1 gene [126], [127]. Notably, a major factor for potential therapeutic strategies involving HO-1 is the presence of a microsatellite polymorphism of (GT)n repeats in human, but not rodent HO-1 promoter [128]. Longer (GT)n repeats are associated with reduced up-regulation of HO-1 and increased susceptibility to various clinically relevant conditions, particularly in cardiovascular diseases [129]. Interestingly, heme arginate infusion has been shown to induce HO-1 protein expression in human volunteers irrespective of the (GT)n polymorphism [130]. Similarly, injection of heme-albumin complexes also up-regulated HO-1 activity in healthy human volunteers, although the (GT)n polymorphism was not considered in this study [131]. Hence, a potential pharmacological HO-1 inducer could be its substrate heme.
    Heme-HO-1 system in macrophages as a target for therapeutic applications Inflammation and oxidative stress play a critical role in the pathogenesis of numerous pathological conditions including cardiovascular or neurological disorders such as atherosclerosis and Alzheimer’s disease. Therefore, anti-inflammatory and antioxidant strategies appear to hold major promise as therapeutic applications in such conditions. It should be noted, however, that strategies, which seemed to be favorable in animal models, could not be translated into the clinic. For example, treatment with antioxidant vitamins turned out to be inefficient in clinical trials [132], [133] and it is conceivable that antioxidant molecules may not reach their indicated target site [134]. Due to the critical role for macrophages in the regulation of inflammation and the major anti-inflammatory potential of HO-1 in these cells, various approaches that apply the heme-HO system in macrophages as a therapeutic target will be discussed in the following.