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Biochemical, Molecular, and Genetic Mechanisms

Anti-Inflammatory Effects of Isoflavones are Dependent on Flow and Human Endothelial Cell PPAR¹

² Department of Pathology, ³ Department of Pharmacology, ⁴ Purdue-UAB Botanical Center, and ⁵ Center for Free Radical Biology, University of Alabama, Birmingham, AL 35294; ⁶ Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261; and ⁷ School of Chemistry, University of St. Andrews, Fife KY16 9ST, Scotland

^* To whom correspondence should be addressed. E-mail: patel{at}path.uab.edu.

The mechanisms by which isoflavones protect against inflammatory vascular disease remain unclear. Our previous observations suggest that one mechanism involves inhibition of monocyte-endothelial cell interactions in a process that is absolutely dependent on flow. The molecular mechanisms involved and the effects of structurally distinct isoflavones on this process are not known and are investigated herein. Using static and flow-dependent monocyte adhesion assays, our data show that exposure of endothelial cells to biologically relevant concentrations of isoflavones inhibits subsequent TNF- induced monocyte adhesion only during flow. This inhibition involved activating endothelial PPAR by stimulating promoter sequences containing the PPAR response element by isoflavones and attenuating antiadhesive effects by siRNA targeting of PPAR. A comparison of structurally distinct isoflavones suggested a critical role for the A-ring. Using chlorinated derivatives of daidzein, a key structural requirement for PPAR agonist activity appears to be the presence of the 7-OH group and the lack of chlorine at the 6- or 8-positions in the A-ring. Collectively, these data support 1) a novel flow-dependent anti-inflammatory mechanism for PPAR ligands in vascular endothelial cells and 2) exemplify the current concepts of nutrients modulating disease via regulating specific cell signaling pathways.

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