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The Down syndrome critical region gene 1 short variant promoters direct vascular bed-specific gene expression during inflammation in mice.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2009 Aug; Vol. 119 (8), pp. 2257-70. Date of Electronic Publication: 2009 Jul 13. - Publication Year :
- 2009
-
Abstract
- Down syndrome critical region gene 1 (DSCR-1) short variant (DSCR-1s) is an inhibitor of calcineurin/NFAT signaling encoded by exons 4-7 of DSCR1. We previously reported that VEGF induces DSCR-1s expression in endothelial cells, which in turn negatively feeds back to attenuate endothelial cell activation. Here, in order to characterize the role of the promoter that drives DSCR-1s expression in mediating inducible expression in vivo and to determine the functional relevance of DSCR-1s in inflammation, we targeted a DNA construct containing 1.7 kb of the human DSCR1s promoter coupled to the lacZ reporter to the hypoxanthine guanine phosphoribosyl transferase (Hprt) locus of mice. We determined that lacZ was uniformly expressed in the endothelium of transgenic embryos but was markedly downregulated postnatally. Systemic administration of VEGF or LPS in adult mice resulted in cyclosporine A-sensitive reactivation of the DSCR1s promoter and endogenous gene expression in a subset of organs, including the heart and brain. The DSCR1s promoter was similarly induced in the endothelium of tumor xenografts. In a mouse model of endotoxemia, DSCR-1s-deficient mice demonstrated increased sepsis mortality, whereas adenovirus-mediated DSCR-1s overexpression protected against LPS-induced lethality. Collectively, these data suggest that the DSCR1s promoter directs vascular bed-specific expression in activated endothelium and that DSCR-1s serves to dampen the host response to infection.
- Subjects :
- Age Factors
Animals
Calcium-Binding Proteins
Cells, Cultured
Endothelial Cells metabolism
Female
GATA2 Transcription Factor physiology
Gene Expression Regulation
Humans
Intracellular Signaling Peptides and Proteins physiology
Lipopolysaccharides toxicity
Male
Mice
Mice, Inbred C57BL
Muscle Proteins physiology
NFATC Transcription Factors physiology
Promoter Regions, Genetic
Vascular Endothelial Growth Factor A pharmacology
Inflammation metabolism
Intracellular Signaling Peptides and Proteins genetics
Muscle Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 119
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 19620774
- Full Text :
- https://doi.org/10.1172/JCI35738