No abstract

Heme oxygenase-1 (HO-1) cleaves the porphyrin ring of heme into carbon monoxide, Fe2+, and biliverdin, which is then converted into bilirubin. Heme-derived Fe2+ induces the expression of the iron-sequestering protein ferritin and activates the ATPase Fe2+-secreting pump, which decrease intracellular free Fe2+ content. Based on the antioxidant effect of bilirubin and that of decreased free cellular Fe2+, we questioned whether HO-1 would modulate the expression of proinflammatory genes associated with endothelial cell (EC) activation. We tested this hypothesis specifically for the genes E-selectin (CD62), ICAM-1 (CD54), and VCAM-1 (CD106). We found that HO-1 overexpression in EC inhibited TNF-α-mediated E-selectin and VCAM-1, but not ICAM-1 expression, as tested at the RNA and protein level. Heme-driven HO-1 expression had similar effects to those of overexpressed HO-1. In addition, HO-1 inhibited the activation of NF-κB, a transcription factor required for TNF-α-mediated up-regulation of these genes in EC. Bilirubin and/or Fe2+ chelation mimicked the effects of HO-1, whereas biliverdin or carbon monoxide did not. In conclusion, HO-1 inhibits the expression of proinflammatory genes associated with EC activation via a mechanism that is associated with the inhibition of NF-κB activation. This effect of HO-1 is mediated by bilirubin and/or by a decrease of free intracellular Fe2+ but probably not by biliverdin or carbon monoxide.

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The influence of applied stress on the measurement of hardness and elastic modulus using nanoindentation methods has been experimentally investigated using special specimens of aluminum alloy 8009 to which controlled stresses could be applied by bending. When analyzed according to standard methods, the nanoindentation data reveal changes in hardness with stress similar to those observed in conventional hardness tests. However, the same analysis shows that the elastic modulus changes with stress by as much as 10%, thus suggesting that the analysis procedure is somehow deficient. Comparison of the real indentation contact areas measured optically to those determined from the nanoindentation data shows that the apparent stress dependence of the modulus results from an underestimation of the contact area by the nanoindentation analysis procedures.