Anti-Inflammatory Effects of Laminar Flow

Abstract

Atherosclerosis occurs most often in the arterial system at locations where blood flow is disturbed, at branches or curved parts of the vessels. This may be because the laminar blood flow stimulates an anti-inflammatory response in the endothelium. Liu et al. show that epoxyeicosatrienoic acids (EETs) are peroxisome proliferator-activated receptor γ (PPARγ) ligands that activate PPARγ transcriptional activity in a reporter assay in bovine aortic endothelial cells (BAECs) and stimulate expression of PPARγ target genes in human umbilical cord endothelial cells (HUVECs) and 3T3-L1 cells. These responses were seen only if soluble epoxide hydrolase (sEH) was inhibited, because this enzyme rapidly metabolizes EETs. Laminar flow also stimulated PPARγ activity in the mammalian two-hybrid assay using BAECs, and inhibition of sEH enhanced this response, whereas overexpression of sEH decreased the response. Laminar flow decreased the abundance and expression of sEH in BAECs and stimulated production of EETs. To confirm that EETs acted through PPARγ, BAECs were treated with an inhibitor of sEH and exogenous EETs in the presence and absence of a PPARγ inhibitor and then treated with tumor necrosis factor-α (TNF-α) to stimulate nuclear factor κβ (NF-κβ) through degradation of IκBα. The presence of EETs (and the sEH inhibitor) prevented TNF-α-mediated degradation of IκBα, and addition of an inhibitor of PPARγ attenuated this anti-inflammatory effect. Thus, production of EETs by endothelial cells and stimulation of an anti-inflammatory pathway through PPARγ may be one mechanism by which laminar flow protects blood vessels from becoming atherosclerotic. Y. Liu, Y. Zhang, K. Schmelzer, T.-S. Lee, X. Fang, Y. Zhu, A. A. Spector, S. Gill, C. Morisseau, B. D. Hammock, J. Y.-J. Shyy, The antiinflammatory effect of laminar flow: The role of PPARγ, epoxyeicosatrienoic acids, and soluble epoxide hydrolase. Proc. Natl. Acad. Sci. U.S.A. 102 , 16747-16752 (2005). [Abstract] [Full Text]