Moreover, mitochondrial translocation of HO-1 can also lead to localized CO production as a result of heme degradation, thus inhibiting electron flow though mitochondrial electron transport chain complex IV (44).
Exposure to Hb and its oxidized products increases heme overload on the AT1 cells. Heme overload induces the expression of HO-1 and iron-sequestering proteins, such as ferritin.
We also found that HbFe21 and HbFe31 activate NF-kB and mitogen-activated protein kinase pathways, as shown by phosphorylation of NF-kB p65 subunit and p44/42, respectively (Figure E3) as noted previously (31).
Exposure to ferric Hb (HbFe31) induced a significant expression in HO-1 protein– (15.1761.04-fold) when compared with HbFe21 (9.3260.76-fold)- induced expression (Figure 2C).
We found a significant enrichment of HO-1 in the mitochondrial, but not in the cytosolic fractions after exposure to HbFe21 and HbFe31 (Figures 3A and 3B).
Similarly, HbFe31 induced a significant expression H-ferritin protein (60.4062.76-fold) when compared with a 25.25 (61.91)-fold induction by HbFe21 (Figure 2D).
Exposure to HbFe21 and HbFe31 did not alter the expression of cytochrome c oxidase IV protein (Figure 3A).
For example, HbFe41 (20 mM), but not HbFe31 or HbFe21, induced cytoskeletal reorganization, inflammation and disrupted barrier integrity in endothelial cells after 8 hours of incubation with the proteins.
Exposure to HbFe41 caused a significant up-regulation of HO-1 within 12 hours when compared with HbFe21 and HbFe31 (Figures 4A and 4B).
We found significant enrichment of HO-1 in mitochondrial fraction after exposure to HbFe31 and HbFe41 (Figure 4C).
Exposure to HbFe41 resulted in a drop in hyperpolarized cell percentage over untreated control, thus indicating a significant mitochondrial depolarization or compromised mitochondrial respiration.
Subsequent RBC lysis leads to release of acellular Hb, which, in turn, damages the alveolar epithelial cells.
We found that Hpx effectively attenuated HO-1 induction by all redox forms of Hb.
Hp attenuated HbFe21- and HbFe31-induced up-regulation of HO-1 and H-ferritin proteins (Figure 2B).
Interestingly, Hp attenuated the HbFe21- and HbFe31-induced HO-1 expression in the mitochondria (Figures 3A and 3B).
However, hemin or LPS-induced mitochondrial accumulation of HO-1 was associated with decreased mitochondrial heme content and reduced expression of heme-sensitive subunit I of complex IV with loss of activity (33).
A recent study indicated that expression of HO-1 targeted to mitochondria attenuated oxidative stress (43).
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.