Alpha1-antitrypsin counteracts heme-induced endothelial cell inflammatory activation, autophagy dysfunction and death
Kukuh Madyaningrana,
Vijith Vijayan,
Christoph Nikolin,
Abid Aljabri,
Srinu Tumpara,
Elena Korenbaum,
Harshit Shah,
Metodi Stankov,
Heiko Fuchs,
Sabina Janciauskiene,
Stephan Immenschuh
Affiliations
Kukuh Madyaningrana
Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany; Faculty of Biotechnology, Universitas Kristen Duta Wacana, Yogyakarta, Indonesia
Vijith Vijayan
Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
Christoph Nikolin
Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
Abid Aljabri
Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
Srinu Tumpara
Department of Pulmonology, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
Elena Korenbaum
Institute for Biophysical Chemistry Hannover Medical School, Hannover, Germany
Harshit Shah
Institute for Pathology, Hannover Medical School, Hannover, Germany
Metodi Stankov
Department for Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany
Heiko Fuchs
Institute of Experimental Ophthalmology, Hannover Medical School, Hannover, Germany
Sabina Janciauskiene
Department of Pulmonology, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
Stephan Immenschuh
Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany; Corresponding author. Institute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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.
