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CREB-mediated IL-6 expression is required for 15(S)-hydroxyeicosatetraenoic acid-induced vascular smooth muscle cell

Koteswara R Chava1, Manjula Karpurapu, Dong Wang

  • 1Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, USA.

Arteriosclerosis, Thrombosis, and Vascular Biology
|April 4, 2009
PubMed
Abstract

Insights

This study reveals that 15(S)-HETE promotes vascular smooth muscle cell (VSMC) migration and neointima formation through a CREB-dependent pathway involving IL-6. These findings highlight a potential therapeutic target for atherosclerosis and restenosis.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Cellular Signaling

Background:

  • Vascular smooth muscle cell (VSMC) migration is critical in atherosclerosis and restenosis.
  • Cyclic AMP response element binding protein (CREB) influences VSMC motility.
  • Lipoxygenase products, like 15(S)-HETE, are implicated in these vascular diseases.

Purpose of the Study:

  • To investigate the role of CREB in 15(S)-HETE-induced VSMC migration.
  • To elucidate the involvement of CREB in neointima formation mediated by 15(S)-HETE.

Main Methods:

  • VSMC migration assays (modified Boyden chamber).
  • Analysis of CREB phosphorylation and signaling pathways (MEK1, JNK1, p38MAPK, ERK1/2).
  • Gene expression and protein analysis (RT-PCR, ELISA) for IL-6.
  • Promoter activity assays and chromatin immunoprecipitation for IL-6 regulation.
  • In vivo studies using balloon injury models and adenovirus-mediated gene transfer (15-LOX2).

Main Results:

  • 15(S)-HETE stimulated VSMC migration in a CREB-dependent manner.
  • MAPK pathways (MEK1, JNK1, p38MAPK) mediated 15(S)-HETE-induced CREB phosphorylation and migration.
  • 15(S)-HETE upregulated IL-6 expression and secretion, which was essential for VSMC migration.
  • CREB directly regulated IL-6 gene expression via the cAMP response element.
  • Inhibition of CREB or IL-6 blocked 15(S)-HETE-induced migration and neointima formation.
  • Overexpression of 15-LOX2 increased 15-HETE production, leading to enhanced IL-6 expression, VSMC migration, and neointima formation.

Conclusions:

  • The 15-lipoxygenase 2 (15-LOX2) and its product 15(S)-HETE play a significant role in VSMC migration and neointima formation.
  • This process is regulated by CREB-mediated induction of IL-6 expression.
  • Targeting the 15-LOX2-15-HETE-CREB-IL-6 axis may offer therapeutic strategies for vascular proliferative diseases.

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