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Regulation of Radixin Gene Expression in Pulmonary Endothelium by LPS and Cyclic Stretch
Author(s) -
Adyshev Djanybek,
Sun Xiaoguang,
Zhang Wei,
Garcia Joe,
Dudek Steven
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.863.17
Subject(s) - moesin , radixin , genome wide association study , ards , promoter , regulation of gene expression , pathogenesis , gene expression , reporter gene , gene , biology , microbiology and biotechnology , genetics , immunology , chemistry , medicine , ezrin , lung , single nucleotide polymorphism , cell , genotype , cytoskeleton
Increased lung vascular permeability is a cardinal feature of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We previously have shown that the ezrin, radixin, and moesin (ERM) proteins differentially participate in agonists‐induced endothelial cell (EC) barrier enhancement and hyperpermeability. In the present study we explore the regulation of radixin gene expression in lung inflammation by disease‐associated genetic variants in the promoter and intronic regions of the RDX. A combination of genomic wide association study (GWAS), in silico analysis, and transfection of RDX promoter luciferase reporter were utilized. We analyzed RDX expression with Genomatix and Haploview for gene regulation and allele linkage disequilibrium (LD), respectively. Inflammatory stimuli LPS and 18% cyclic stretch (a model of mechanical lung injury) each time‐dependently modulate both the protein expression of radixin and phosphorylation of ERMs. A GWAS study of African Americans identified one promoter (rs1792789) and two intronic variants of RDX that were significantly associated with ALI and in high LD with each other. In silico analysis predicted that rs1792789 significantly influences binding of several transcription factors to the RDX promoter. LPS increased the activity of a RDX wt promoter reporter (2.4 fold), but this induction was reduced in EC transfected with a RDX promoter containing rs1792789. The current study characterizes the regulation of expression of RDX by inflammatory disease‐associated polymorphisms and acute inflammatory stimuli, and advances our understanding of how RDX levels are regulated during lung injury pathogenesis.