Vascular-Directed Tissue Factor Pathway Inhibitor Overexpression Regulates Plasma Cholesterol and Reduces Atherosclerotic Plaque Development

• Published in: Circulation research Vol. 105; no. 7; pp. 713 - 720
• Main Authors: Pan, Shuchong, White, Thomas A, Witt, Tyra A, Chiriac, Anca, Mueske, Cheri S, Simari, Robert D
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 25.09.2009; Lippincott Williams & Wilkins
• Subjects: Animals; Aorta - metabolism; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis (general aspects, experimental research); Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Atherosclerosis - prevention & control; Biological and medical sciences; Biological Transport; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured; Cholesterol, Dietary - blood; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Heparan Sulfate Proteoglycans - metabolism; Heparin Lyase - metabolism; Humans; Lipoproteins - genetics; Lipoproteins - metabolism; Lipoproteins, VLDL - blood; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microfilament Proteins - genetics; Muscle Proteins - genetics; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Receptors, LDL - genetics; Receptors, LDL - metabolism; RNA Interference; Time Factors; Transfection; Triglycerides - blood; Up-Regulation; Vertebrates: cardiovascular system; Coagulation; Tissue factor; Gene overexpression; Lipids; Cardiovascular disease; Lipoprotein; Cholesterol; Vascular disease; Vertebrata; Mammalia; Atherosclerotic plaque; murine models; Atherosclerosis; Development; Inhibitor; Models; Circulatory system; lipoproteins
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.195016

RATIONALE: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. METHODS AND RESULTS:On a high-fat diet, smooth muscle 22α (SM22α)-TFPI/apoE mice were shown to have less aortic plaque burden compared to apoE mice. Unexpectedly, SM22α-TFPI/apoE had lower plasma cholesterol levels compared to apoE mice. Furthermore, SM22α-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 SM22α-TFPI and wild-type mice. Mouse aortic smooth muscle cells from SM22α-TFPI mice demonstrated higher VLDL binding and internalization compared to those from wild-type mice. Because SM22α-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.