| Autor: |
Kukuh Madyaningrana, Vijith Vijayan, Christoph Nikolin, Abid Aljabri, Srinu Tumpara, Elena Korenbaum, Harshit Shah, Metodi Stankov, Heiko Fuchs, Sabina Janciauskiene, Stephan Immenschuh |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Redox Biology, Vol 46, Iss , Pp 102060- (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2213-2317 |
| DOI: |
10.1016/j.redox.2021.102060 |
| Popis: |
Free heme toxicity in the vascular endothelium is critical for the pathogenesis of hemolytic disorders including sickle cell disease. In the current study, it is demonstrated that human alpha1-antitrypsin (A1AT), a serine protease inhibitor with high binding-affinity for heme, rescues endothelial cell (EC) injury caused by free heme. A1AT provided endothelial protection against free heme toxicity via a pathway that differs from human serum albumin and hemopexin, two prototypical heme-binding proteins. A1AT inhibited heme-mediated pro-inflammatory activation and death of ECs, but did not affect the increase in intracellular heme levels and up-regulation of the heme-inducible enzyme heme oxygenase-1. Moreover, A1AT reduced heme-mediated generation of mitochondrial reactive oxygen species. Extracellular free heme led to an increased up-take of A1AT by ECs, which was detected in lysosomes and was found to reduce heme-dependent alkalization of these organelles. Finally, A1AT was able to restore heme-dependent dysfunctional autophagy in ECs. Taken together, our findings show that A1AT rescues ECs from free heme-mediated pro-inflammatory activation, cell death and dysfunctional autophagy. Hence, A1AT therapy may be useful in the treatment of hemolytic disorders such as sickle cell disease. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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