Abstract 1422: Candesartan-induced Upregulation Of Transcriptional Regulator Yin Yang 1 Blocks Leukocyte-endothelial Interaction Under Physiological Flow.

Abstract

[Objective] Transcriptional control of inflammation-relevant genes plays an important role in atherosclerosis. We have reported a dominant role of Yin Yang 1 (YY1), a transcriptional regulator, in proliferation of vascular smooth muscle cells (Santiago FS, Ishii H, et al. Circ Res in press). However, its effect in vascular endothelium remains unclear. Recent observation points a novel “genomic” effect of Angiotensin II to influence inflammation. In this study, we examined a potential contribution of YY1 in angiotensin type II receptor blocker (ARB)-mediated modulation of leukocyte-endothelial adhesion under flow condition. [Methods and Results] Human umbilical vein endothelial cells (HUVEC) were co-incubated in the presence or absence of candesartan, an ARB (1 uM) for 4 hours with TNFα (5 ng/ml). Treatment with candesartan dramatically inhibited THP-1 cell adhesion to TNFα-activated HUVEC under static (p <0.01) and flow conditions (p <0.05). We documented that upregulation of YY1 mRNA after candesartan treatment. To examine a role for YY1 in leukocyte-endothelial interaction, YY1 was overexpressed via recombinant adenovirus. The expression levels of VCAM-1 was significantly decreased in HUVEC treated with adenovirus YY1. In addition, adenovirus YY1 blocked THP-1 adhesion to TNFα-activated HUVEC under flow conditions (TNFα, 8.40±0.64/HPF; TNFα+candesartan, 1.93±0.54/HPF; p <0.0001). The expression level of phosphorylated-JNK, as determined by western blotting analysis, was reduced following YY1 transfection. In contrast, YY1 inhibition by YY1 siRNA did not influence leukocyte-endothelial adhesion and the expression of adhesion molecules. [Conclusion] We demonstrated that candesartan treatment upregulated YY1 in HUVEC and inhibited leukocyte-endothelial adhesion by inhibition of VCAM-1 expression. Our findings suggest a novel anti-inflammatory effect of ARB via YY1-dependent mechanisms.