Hypoxia inducible factors in hereditary hemorrhagic telangiectasia – analysis of human and murine models

Freya Droege; Tristan Leu; Jonah Bosserhoff; Jadwiga Jablonska; Joachim Fandrey; Stephan Lang; Urban Geisthoff; Anna Wrobeln

doi:10.1055/s-0042-1746977

Laryngo-Rhino-Otologie, Table of Contents

CC BY-NC-ND 4.0 · Laryngorhinootologie 2022; 101(S 02): S243-S244
DOI: 10.1055/s-0042-1746977

Poster

Rhinology

Hypoxia inducible factors in hereditary hemorrhagic telangiectasia – analysis of human and murine models

Authors

Freya Droege

¹Department of Otorhinolaryngology, Head and Neck Surgery, Essen University Hospital Essen
Tristan Leu

²Institut für Physiologie, Universität Duisburg-Essen, Universitätsklinik Essen Essen
Jonah Bosserhoff

²Institut für Physiologie, Universität Duisburg-Essen, Universitätsklinik Essen Essen
Jadwiga Jablonska

³Translational Oncology, Department of Otorhinolaryngology, University Hospital Essen Essen
Joachim Fandrey

²Institut für Physiologie, Universität Duisburg-Essen, Universitätsklinik Essen Essen
Stephan Lang

¹Department of Otorhinolaryngology, Head and Neck Surgery, Essen University Hospital Essen
Urban Geisthoff

⁴Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Marburg Marburg
Anna Wrobeln

²Institut für Physiologie, Universität Duisburg-Essen, Universitätsklinik Essen Essen

Abstract

Full Text

Introduction Mutations in genes (especially ALK-1 and endoglin) whose encoded proteins are involved in the transforming growth factor β (TGF-β) family signaling lead to hereditary hemorrhagic telangiectasia, a rare disease of vascular endothelial cells. Hypoxia inducible factors (HIF) are known to interact with TGF-β signaling pathway and have an influence on angiogenesis. The aim of this study was to understand HIF regulation in patients with HHT.

Methods Within this study, HIF and their up- and downstream-regulated genes were analyzed in whole blood samples from patients with HHT as well as in organs from HHT simulating knockout-mice.

Results In total, 66 patients with HHT and 26 healthy controls were included in this study. The analysis revealed a significant lower expression of HIF-1 alpha (α) mRNA in patients with HHT compared to the healthy controls (p< 0.01). There was no correlation between the measured epistaxis severity (Epistaxis Severity Score, ESS) and HIF-1α expression (p >0.05). Genes upstream from HIF-1α in the inflammation response (e.g. nuclear factor kappa-light-chain-enhancer of activated B-cells; NFκB) were unchanged (p>0.05), whereas HIF-1α target genes were partly significant downregulated (e.g. interleukin 6; p<0.01). Reflecting human samples, organs of HHT-mice (n=17) showed decreased HIF-1α in intestine, lung and brain on protein level compared to wildtype siblings (n=14).

Conclusion Compared to healthy controls a reduced HIF-1α protein accumulation was seen in human and murine HHT models.Further studies have to clarify the mechanisms behind these interesting findings. Moreover, investigations may identify HIF-stabilization as a possible therapeutic target in HHT patients.