Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of both tissue-type and urokinase-type plasminogen activators. The balance between plasminogen activators and PAI-1 plays an important role in several physiological and pathophysiological processes such as atherosclerosis or thrombosis. Since these conditions are associated with hypoxia, the influence of low O2 tension on the expression of PAI-1 mRNA and protein was studied in primary cultured rat hepatocytes as a model system. The hypoxia-sensitive PAI-1 promoter region was localized and found to contain two putative hypoxia response elements (HRE). A detailed analysis revealed that the HRE-2 was most critical for induction by hypoxia and binding of hypoxia-inducible factor-1 (HIF-1) while HRE-2 bound upstream stimulatory factors (USF-1 and USF-2). Further, we also showed that HIF-1 was involved in the insulin- and thrombin-dependent upregulation of PAI-1. In contrast to HIF-1, USF-2 functioned as an inhibitor of PAI-1 transcription in primary hepatocytes via an as yet not completly understood mechanism. Thus, PAI-1 induction via HIF-1 appears to be crucial for many clinical conditions associated with O2 deficiency. The further aim of this project is to unravel the role of USF within this cenario.

Fig. 2 Regulation of plasminogen activator inhibitor 1 (PAI-1) gene expression by hypoxia. See text for details. The 766 bp rat PAI-1 promoter with its footprinted sites (A-G) is shown. Inside the C-site two hypoxia responsive elements (HRE) were identified. Under hypoxia HRE-2 bound the heterodimeric transcription factor hypoxia inducible factor 1 (HIF-1) consisting of HIF-1a and HIF-1ß whereas the HRE-1 bound USF.