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CREB‐MEDIATED IL‐6 EXPRESSION IS REQUIRED FOR 15(S)‐HYDROXYEICOSATETRAENOIC ACID‐INDUCED VASCULAR SMOOTH MUSCLE CELL MIGRATION
Author(s) -
Chava Koteswara Rao,
Karpurapu Manjula,
Wang Dong,
Bhanoori Manjula,
Sridharan Venkatesh Kundumani,
Rao Gadiparthi N
Publication year - 2009
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.23.1_supplement.699.2
Subject(s) - creb , neointima , vascular smooth muscle , angiotensin ii , chemistry , microbiology and biotechnology , medicine , endocrinology , biology , restenosis , transcription factor , biochemistry , smooth muscle , stent , blood pressure , gene
Migration of vascular smooth muscle cells (VSMC) from media to intima is a key event in the pathophysiology of atherosclerosis and restenosis. Cyclic AMP response element binding protein (CREB) has been implicated in the regulation of VSMC growth and motility in response to thrombin and angiotensin II. In this study, we tested the role of CREB in an oxidized lipid molecule, 15(S)‐HETE‐induced VSMC migration and injury‐induced restenosis. 15(S)‐HETE stimulated VSMC migration in a CREB‐dependent manner, as measured by the modified Boyden chamber method. Blockade of MEK1, JNK1 or p38MAPK inhibited 15(S)‐HETE‐induced CREB phosphorylation and VSMC migration. 15(S)‐HETE induced expression and secretion of interleukin‐6 (IL‐6), as analyzed by RT‐PCR and ELISA, respectively. Neutralizing anti‐IL‐6 antibodies blocked 15(S)‐HETE‐induced VSMC migration. Adenoviral mediated expression of dominant negative MEK1, JNK1, p38MAPK or CREB suppressed 15(S)‐HETE induced IL‐6 expression in VSMC. Serial 5′‐deletions and site‐directed mutagenesis analysis in an IL‐6 promoter‐dependent luciferase reporter system showed that cAMP response element is essential for 15(S)‐HETE‐induced IL‐6 expression. Dominant negative CREB also suppressed balloon injury‐induced IL‐6 expression and neointima formation. Thus, these results suggest a role for MAPK‐dependent CREB‐mediated IL‐6 expression in 15(S)‐HETE‐induced VSMC migration. These findings also suggest a role for CREB in balloon injury‐induced IL‐6 expression and neointima formation.