15-Lipoxygenase Promotes Chronic Hypoxia–Induced Pulmonary Artery Inflammation via Positive Interaction With Nuclear Factor-κBSignificance
Objective—Our laboratory has previously demonstrated that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) is involved in hypoxic pulmonary arterial hypertension. Chronic hypoxia–induced vascular inflammation has been considered as an important stage in the development of pulmonary arterial hypertension. Here, we determined the contribution of 15-HETE in the hypoxia–induced pulmonary vascular inflammation.
Approach and Results—Chronic hypoxia–induced monocyte/macrophage infiltration and the expressions of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were analyzed in hypoxic rat model and cultured pulmonary arterial endothelium cells using immunochemistry methods. We found that monocyte/macrophage infiltration and the expressions of intercellular adhesion molecules under hypoxia were markedly inhibited by 15-HETE inhibitors or 15-LO1/2 small interfering RNA. In addition, exogenous 15-HETE enhanced the expression of both adhesion molecules in pulmonary arterial endothelium cells in a time-dependent manner. Hypoxia–induced 15-LO1/2 expression in rat pulmonary arterial endothelium cells was significantly abolished by nuclear factor-κB inhibitors. Meanwhile, nuclear factor-κB activity was enhanced prominently by the 15-LO1/2 product, 15-HETE, suggesting a positive feedback mechanism.
Conclusions—Taken together, our results suggest that chronic hypoxia promotes monocyte infiltration into the vasculature and adhesion molecules upregulation in pulmonary arterial endothelium cells via a positive interaction between 15-LO/15-HETE and nuclear factor-κB. Our study revealed a novel mechanism underlying hypoxia–induced pulmonary arterial inflammation and suggested new therapeutic strategies targeting 15-LO/15-HETE and nuclear factor-κB in the treatment of pulmonary arterial hypertension.
- adhesion molecules
- chronic hypoxia
- 15-hydroxyeicosatetraenoic acid
- nuclear factor-κB
- pulmonary arterial inflammation
- Received June 20, 2012.
- Accepted February 22, 2013.
- © 2013 American Heart Association, Inc.