Dietary lipid lowering reduces tissue factor expression in rabbit atheroma

Background-The mechanisms by which lipid lowering reduces the incidence of acute thrombotic complications of coronary atheroma in clinical trials rema ins unknown. Tissue factor (TF) overexpressed in atheroma may accelerate th rombus formation at the sites of plaque disruption. A cell surface cytokine CD40 ligand (CD40L) enhances TF expression in vitro. Methods and Results-To test the hypothesis that lipid lowering reduces TF e xpression and activity, we produced atheroma in rabbit aortas by balloon in jury and cholesterol feeding for 4 months (Baseline group, n=15), followed by either a chow diet (Low group, n=10) or a continued high-cholesterol die t for 16 months (High group, n=5). Immunolocalization of TF, CD40L, and its receptor CD40 was quantified by computer-assisted color image analysis. Ma crophages in atheroma of the Baseline and High groups strongly expressed TF . Intimal smooth muscle cells and endothelial cells also contained immunore active TF, Regions of expression of CD40L and CD40 colocalized with TF. Pro tein expression of TF diminished substantially in the Low group in associat ion with reduced expression of CD40L and CD40, In situ binding of TF to fac tors VIIa and X, detected by digoxigenin-labeled factors VIIa and X, coloca lized with TF protein in atheroma and decreased after lipid lowering. We al so determined reduced TF biological activity in the Low group by use of a c hromogenic assay. The level of TF mRNA detected by reverse transcription-po lymerase chain reaction also decreased after lipid lowering. Conclusions-These results suggest decreased expression and activity of TF a s a novel mechanism of reduced incidence of thrombotic complications of ath erosclerosis by lipid lowering.