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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4177-4185
Induction of the Plasminogen Activator Inhibitor-1 Gene Expression by
Mild Hypoxia Via a Hypoxia Response Element Binding the
Hypoxia-Inducible Factor-1 in Rat Hepatocytes
Thomas Kietzmann,
Ulrike Roth, and
Kurt Jungermann
From the Institut für Biochemie und Molekulare Zellbiologie,
Göttingen, Germany.
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.
Because these conditions are associated with hypoxia, it was the aim of
the present study to investigate the influence of low O2
tension on the expression of PAI-1 mRNA and protein using primary
cultured rat hepatocytes as a model system. We found that PAI-1 mRNA
and protein were induced by mild hypoxia (8% O2). The
hypoxia-dependent PAI-1 mRNA induction was transcriptionally regulated
because it was inhibited by actinomycin D (ActD). Luciferase (LUC)
reporter gene constructs driven by about 800 bp of the
5'-flanking region of the rat PAI-1 gene were transiently
transfected into primary rat hepatocytes; mild hypoxia caused a 3-fold
induction, which was mediated by the PAI-1 promoter region -175/-158
containing 2 putative hypoxia response elements (HRE) binding the
hypoxia-inducible factor (HIF-1). Mutation of the HRE-1 (-175/-168) or
HRE-2 (-165/-158) also abolished the induction by mild hypoxia.
Cotransfection of a HIF-1 vector and the PAI-1-LUC constructs, as
well as gel shift assays, showed that the HRE-2 of the PAI-1 promoter
was most critical for induction by hypoxia and HIF-1 binding. Thus,
PAI-1 induction by mild hypoxia via a HIF-1 binding HRE in the rat
PAI-1 promoter appears to be the mechanism causing the increase in
PAI-1 in many clinical conditions associated with O2 deficiency.
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