Altered hypoxia inducible factor regulation in hereditary haemorrhagic telangiectasia

Abstract

Patients with hereditary haemorrhagic telangiectasia (HHT), also known as Rendu–Osler–Weber syndrome, suffer from the consequences of abnormal vessel structures. These structures can lead to haemorrhages or shunt effects in liver, lungs and brain. This inherited and rare disease is characterized by mutations affecting the transforming growth factor-β (TGF-β)/Bone Morphogenetic Protein (BMP) pathway that results in arteriovenous malformations and studies indicate an impaired immune response. The mechanism underlying this altered immune response in HHT patients is still unknown. TGF-β interacts with hypoxia inducible factors (HIF), which both orchestrate inflammatory and angiogenic processes. Therefore, we analysed the expression of HIF and related genes in whole blood samples from HHT patients. We could show significantly decreased expression of HIF-1α on the mRNA and protein level. However, commonly known upstream regulators of HIF-1α in inflammatory responses were not affected, whereas HIF-1α target genes were significantly downregulated. There was no correlation between HIF1A or HIF2A gene expression and the severity of HHT detected. Our results represent a rare case of HIF-1α downregulation in a human disease, which underlines the relevance of HIFs in HHT. The study indicates an interaction of the known mutation in HHT and the dysregulation of HIF-1α in HHT patients, which might contribute to the clinical phenotype.

Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitor Improves Leukocyte Energy Metabolism in Hereditary Hemorrhagic Telangiectasia

“…The reduced expression of HIF-1α in leukocytes of HHT patients may explain some observations of immune defects in HHT patients [ 26 ]. Phosphoglycerate kinase 1 (PGK1) catalyzes the removal of phosphate from 1, 3-bisphosphoglycerate to ADP to form 3-phosphoglycerate and ATP as a sub-step of glycolysis.…”

“…Several studies have shown immune cell dysfunction in the absence of HIFs [ 24 , 25 ]. Recently, our group quantified, for the first time ever, the expression of HIF-1α and HIF target genes in whole blood samples from HHT patients [ 26 ]. We showed a significant reduction in the expression of HIF1A gene, HIF-1α protein and HIF-1α target genes in whole blood of HHT patients.…”