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 language | English (US) |
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Pages (from-to) | 2301-2307 |
Number of pages | 7 |
Journal | Arteriosclerosis, thrombosis, and vascular biology |
Volume | 25 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2005 |
Externally published | Yes |
Keywords
- 12/15-lipoxygenase
- Endothelium
- ICAM-1
- RhoA
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine