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Tissue‐ and agonist‐specific regulation of human and murine plasminogen activator inhibitor‐1 promoters in transgenic mice
Author(s) -
Eren M.,
Painter C. A.,
Gleaves L. A.,
Schoenhard J. A.,
Atkinson J. B.,
Brown N. J.,
Vaughan D. E.
Publication year - 2003
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1046/j.1538-7836.2003.00437.x
Subject(s) - promoter , transgene , biology , microbiology and biotechnology , spleen , activator (genetics) , genetically modified mouse , heterologous , in vivo , green fluorescent protein , gene expression , gene , immunology , biochemistry , genetics
Summary. Numerous studies have described regulatory factors and sequences that control transcriptional responses in vitro. However, there is a paucity of information on the qualitative and quantitative regulation of heterologous promoters using transgenic strategies. In order to investigate the physiological regulation of human plasminogen activator inhibitor type‐1 (hPAI‐1) expression in vivo compared to murine PAI‐1 (mPAI‐1) and to test the physiological relevance of regulatory mechanisms described in vitro , we generated transgenic mice expressing enhanced green fluorescent protein (EGFP) driven by the proximal −2.9 kb of the hPAI‐1 promoter. Transgenic animals were treated with Ang II, TGF‐β1 and lipopolysaccharide (LPS) to compare the relative activation of the human and murine PAI‐1 promoters. Ang II increased EGFP expression most effectively in brain, kidney and spleen, while mPAI‐1 expression was quantitatively enhanced most prominently in heart and spleen. TGF‐β1 failed to induce activation of the hPAI‐1 promoter but potently stimulated mPAI‐1 in kidney and spleen. LPS administration triggered robust expression of mPAI‐1 in liver, kidney, pancreas, spleen and lung, while EGFP was induced only modestly in heart and kidney. These results indicate that the transcriptional response of the endogenous mPAI‐1 promoter varies widely in terms of location and magnitude of response to specific stimuli. Moreover, the physiological regulation of PAI‐1 expression likely involves a complex interaction of transcription factors and DNA sequences that are not adequately replicated by in vitro functional studies focused on the proximal −2.9 kb promoter.