Vascular-directed tissue factor pathway inhibitor overexpression regulates plasma cholesterol and reduces atherosclerotic plaque development.
BACKGROUND
Tissue factor pathway inhibitor (TFPI) is a potent regulator of the tissue factor pathway and is found in plasma in association with lipoproteins.


OBJECTIVE
To determine the role of TFPI in the development of atherosclerosis, we bred mice which overexpress TFPI into the apolipoprotein E-deficient (apoE(-/-)) background.


RESULTS
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.


CONCLUSIONS
These studies suggest that overexpression of TFPI lowers plasma cholesterol through the interaction of its carboxyl terminus with lipoproteins and heparan sulfate proteoglycans.
Pan
Shuchong
S
Division of Cardiovascular Diseases and Internal Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minn. 55905, USA.
White
Thomas A
TA
Witt
Tyra A
TA
Chiriac
Anca
A
Mueske
Cheri S
CS
Simari
Robert D
RD
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001692:Biological Transport; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000097:blood*; D004195:Disease Models, Animal; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D019763:Heparin Lyase / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D019812:Heparan Sulfate Proteoglycans; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D008840:Microfilament Proteins; D009124:Muscle Proteins; D011973:Receptors, LDL; D014280:Triglycerides; C036053:VLDL receptor; C051928:lipoprotein-associated coagulation inhibitor; C051615:transgelin; D019763:Heparin Lyase