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Transcriptional mechanisms that mediate upregulation of thrombospondin‐1 expression by leptin in vascular smooth muscle cells
Author(s) -
Sahu Soumyadip,
Chavez Ronaldo,
Ganguly Rituparna,
Raman Priya
Publication year - 2013
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.27.1_supplement.1138.9
Subject(s) - leptin , creb , downregulation and upregulation , transcription factor , microbiology and biotechnology , leptin receptor , chemistry , vascular smooth muscle , promoter , biology , medicine , endocrinology , gene expression , gene , biochemistry , smooth muscle , obesity
Hyperleptinemia is an important pathophysiological trigger for development of atherosclerotic complications. However, molecular mechanisms activated by leptin that modulate vascular gene expression are poorly understood. We recently reported a novel regulatory effect of leptin via JAK2/ERK/JNK signaling on thrombospondin‐1 (TSP‐1), a potent proatherogenic and antiangiogenic matricellular protein, in human aortic smooth muscle cells (HASMC). The goal of this study was to explore transcriptional mechanism(s) that mediate TSP‐1 upregulation by leptin. Promoter deletion analysis revealed a long fragment (−1270/+750) that is required for activation of TSP‐1 promoter by leptin in HASMC. Using protein/DNA array (Panomics), we identified several potential transcription factors (TFs: GAS/ISRE, IRF1, STAT1/3, CREB) activated by leptin, with predicted binding sites in distal fragment of TSP‐1 promoter determined by MatInspector (Genomatix). These results were further confirmed in EMSA where leptin increased IRF1 and CREB binding activity to TSP‐1 promoter. Additionally, JAK2‐, ERK‐, and JNK‐specific inhibitors significantly attenuated activation of IRF1 and CREB‐binding protein complexes in leptin treated cells. These data suggest that specific TFs such as IRF1 and CREB mediate leptin induced TSP‐1 transcription which may contribute to vascular complications associated with hyperleptinemia.