Article

Vascular-directed tissue factor pathway inhibitor overexpression regulates plasma cholesterol and reduces atherosclerotic plaque development.

Division of Cardiovascular Diseases and Internal Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minn. 55905, USA.
Circulation Research (impact factor: 9.49). 09/2009; 105(7):713-20, 8 p following 720. DOI:10.1161/CIRCRESAHA.109.195016 pp.713-20, 8 p following 720
Source: PubMed

ABSTRACT Tissue factor pathway inhibitor (TFPI) is a potent regulator of the tissue factor pathway and is found in plasma in association with lipoproteins.
To determine the role of TFPI in the development of atherosclerosis, we bred mice which overexpress TFPI into the apolipoprotein E-deficient (apoE(-/-)) background.
On a high-fat diet, smooth muscle 22alpha (SM22alpha)-TFPI/apoE(-/-) mice were shown to have less aortic plaque burden compared to apoE(-/-) mice. Unexpectedly, SM22alpha-TFPI/apoE(-/-) had lower plasma cholesterol levels compared to apoE(-/-) mice. Furthermore, SM22alpha-TFPI mice fed a high-fat diet had lower cholesterol levels than did wild-type mice. Because TFPI is associated with lipoproteins and its carboxyl terminus (TFPIct) has been shown to be a ligand for the very-low-density lipoprotein (VLDL) receptor, we hypothesized that TFPI overexpression may regulate lipoprotein distribution. We quantified VLDL binding and uptake in vitro in mouse aortic smooth muscle cells from SM22alpha-TFPI and wild-type mice. Mouse aortic smooth muscle cells from SM22alpha-TFPI mice demonstrated higher VLDL binding and internalization compared to those from wild-type mice. Because SM22alpha-TFPI mice have increased circulating levels of TFPI antigen, we examined whether TFPIct may act to alter lipoprotein distribution. In vitro, TFPIct increased VLDL binding, uptake, and degradation in murine embryonic fibroblasts. Furthermore, this effect was blocked by heparinase treatment. In vivo, systemic administration of TFPIct reduced plasma cholesterol levels in apoE(-/-) mice.
These studies suggest that overexpression of TFPI lowers plasma cholesterol through the interaction of its carboxyl terminus with lipoproteins and heparan sulfate proteoglycans.

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Keywords

aortic plaque burden
 
carboxyl terminus
 
heparan sulfate proteoglycans
 
heparinase treatment
 
higher VLDL binding
 
lipoprotein distribution
 
murine embryonic fibroblasts
 
overexpress TFPI
 
plasma cholesterol
 
plasma cholesterol levels
 
SM22alpha-TFPI mice
 
SM22alpha-TFPI/apoE(-/-)
 
smooth muscle 22alpha
 
systemic administration
 
TFPI overexpression
 
tissue factor pathway
 
Tissue factor pathway inhibitor
 
very-low-density lipoprotein
 
VLDL binding
 
wild-type mice