P130	Human HIF-3α is a novel inhibitor of angiogenesis.
S.Bonello, A.Petry, R.S.Belaiba, Chr.Zähringer, T.Djordjevic, J.Hess, A.Görlach
Experimentelle Kinderkardiologie, Deutsches Herzzentrum München an der TU München, München, DE.

Angiogenesis is centrally involved in the adaptation of many organs to low oxygen conditions and plays an important role in tumor progression. The hypoxia-inducible transcription factor family HIF is centrally involved in the cellular response to hypoxia and is an important regulator of angiogenesis. HIFs consist of an inducible α-subunit and a constitutively expressed β-subunit (ARNT). HIF-1alpha and HIF-2alpha are activated by low oxygen levels, upregulate the expression of many genes including vascular endothelial growth factor (VEGF) and plasminogen activator inhibitor-1 (PAI-1) and promote the angiogenic response. Recently, a novel family member, HIF-3alpha, has been identified. However, the role of human HIF-3alpha in the vasculature and in the hypoxic response is not clear yet. We therefore aimed to investigate the role of human HIF-3alpha in the hypoxic response of vascular cells and in the regulation of angiogenesis. Human HIF-3alpha was expressed in human smooth muscle cells and microvascular endothelial cells. Similar to HIF-1alpha, it interacted with ARNT as was shown by bimolecular fluorescence complementation assay and coimmunoprecipitation. However, in contrast to HIF-1alpha, HIF-3alpha decreased HIF activity in a dose-dependent manner. Furthermore, overexpression of HIF-3alpha prevented PAI-1 and VEGF secretion by hypoxia in smooth muscle cells, and inhibited endothelial proliferation as well as angiogenesis. These results show that human HIF-3alpha dimerises with ARNT but acts as an inhibitor of HIF activity, hypoxic gene expression, proliferation and angiogenesis. Thus, HIF-3alpha may limit cellular adaptative processes to hypoxia such as angiogenesis and may act as an inihibitor of tumor progression.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.