12/15-Lipoxygenase regulates intercellular adhesion molecule-1 expression and monocyte adhesion to endothelium through activation of RhoA and nuclear factor-κB

David T. Bolick, A. Wayne Orr, Angela Whetzel, Suseela Srinivasan, Melissa E. Hatley, Martin A. Schwartz, Catherine C. Hedrick

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Background - 12/15-lipoxygenase (12/15-LO) activity leads to the production of the proinflammatory eicosanoids 12-S-hydroxyeicosatetraenoic acid (12SHETE) and 13-S-hydroxyoctadecadienoic acid. We have previously shown a 3.5-fold increase in endothelial intercellular adhesion molecule (ICAM)-1 expression in mice overexpressing the 12/15-LO gene. We examined whether 12/15-LO activity regulated endothelial ICAM-1 expression. Methods and Results - Freshly isolated aortic endothelial cells (EC) from 12/15-LO transgenic mice had significantly greater nuclear factor-κB (NF-κB) activation and ICAM mRNA expression compared with C57BL/6J control. 12/15-LO transgenic EC showed elevated RhoA activity, and inhibition of RhoA using either C3 toxin or the Rho-kinase inhibitor Y-27632 blocked NF-κB activation, ICAM-1 induction, and monocyte adhesion. Furthermore, we show that 12SHETE activates protein kinase Cα, which forms a complex with active RhoA and is required for NF-κB-dependent ICAM expression in response to 12SHETE. Conclusions - The 12/15-LO pathway stimulates ICAM-1 expression through the RhoA/protein kinase Cα-dependent activation of NF-κB. These findings identify a major signaling pathway in EC through which 12/15-LO contributes to vascular inflammation and atherosclerosis.

Original languageEnglish (US)
Pages (from-to)2301-2307
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume25
Issue number11
DOIs
StatePublished - Nov 2005
Externally publishedYes

Keywords

  • 12/15-lipoxygenase
  • Endothelium
  • ICAM-1
  • RhoA

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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