Abstract 1716: Targeted Vascular Overexpression of TFPI Reduces Plaque Burden in apoE Deficient Mice in a Cholesterol-Dependent Manner
Tissue factor pathway inhibitor (TFPI) is a Kunitz type proteinase that regulates the extrinsic pathway of coagulation by inhibiting the factor VIIa/tissue factor (TF) catalytic complex. TFPI is known to regulate tissue factor activity in animal models of vascular disease and in human atherosclerotic plaque. TFPI is found circulating in association with lipoproteins. We have previously described the effects of vascular overexpression of TFPI on local thrombosis. To determine the role of local TFPI overexpression on atherosclerotic plaque development, we bred SM22α-TFPI mice into the apo E deficient line. The resulting mice which lack the apo E allele and contain the SM22α-TFPI transgene have higher levels TFPI in plasma compared to apo E deficient mice, whereas TFPI activities remain the same. After 20 weeks of western high fat diet, SM22α-TFPI/apo E−/− mice were shown to have 63% less plaque burden within their aortas compared to apo E deficient mice (p<0.05). Measurement of total cholesterol levels from these mice provided unexpected results. Mice that contained the SM22α-TFPI transgene (in the apoE deficient line) had lower serum cholesterols at 5 weeks and 20 weeks compared with apo E deficient on a high fat western diet (see Table⇓). We repeated these studies using FPLC of mouse plasma at 5 weeks. FPLC data suggests that the mice containing the TFPI transgene had lower cholesterol in VLDL fractions than did their apo E−/− counterparts. These studies suggest that vascular overexpression of TFPI reduces plaque burden and may play a role in regulating lipid metabolism in apo E deficient mice fed a western diet. Ongoing studies are aimed at defining the mechanism of this effect.