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

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.

SUBMITTER: Pan S

PROVIDER: S-EPMC2852138 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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

Pan Shuchong S White Thomas A TA Witt Tyra A TA Chiriac Anca A Mueske Cheri S CS Simari Robert D RD

Circulation research 20090827 7

<h4>Rationale</h4>Tissue factor pathway inhibitor (TFPI) is a potent regulator of the tissue factor pathway and is found in plasma in association with lipoproteins.<h4>Objective</h4>To determine the role of TFPI in the development of atherosclerosis, we bred mice which overexpress TFPI into the apolipoprotein E-deficient (apoE(-/-)) background.<h4>Methods and results</h4>On a high-fat diet, smooth muscle 22alpha (SM22alpha)-TFPI/apoE(-/-) mice were shown to have less aortic plaque burden compare ...[more]

PMID: 19713537

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Project description:Objective: Elevated plasma cholesterol concentrations contributes to ischemic cardiovascular diseases. Recently, we showed that inhibiting hepatic (pro)renin receptor [(P)RR] attenuated diet-induced hypercholesterolemia and hypertriglyceridemia in low-density lipoprotein receptor (LDLR) deficient mice. The purpose of this study was to determine whether inhibiting hepatic (P)RR could attenuate atherosclerosis. Approach and Results: Eight-week-old male LDLR-/- mice were injected with either saline or N-acetylgalactosamine-modified antisense oligonucleotides (G-ASOs) primarily targeting hepatic (P)RR and were fed a western-type diet (WTD) for 16 weeks. (P)RR G-ASOs markedly reduced plasma cholesterol concentrations from 2,211 ± 146 to 1,128 ± 121 mg/dL. Fast protein liquid chromatography (FPLC) analyses revealed that cholesterol in very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL)/LDL fraction were potently reduced by (P)RR G-ASOs. Moreover, (P)RR G-ASOs reduced plasma triglyceride concentrations by more than 80%. Strikingly, despite marked reduction in plasma lipid concentrations, atherosclerosis was not reduced but rather increased in these mice. Further testing in ApoE-/- mice confirmed that (P)RR G-ASOs reduced plasma lipid concentrations but not atherosclerosis. Transcriptomic analysis of the aortas revealed that (P)RR G-ASOs induced the expression of the genes involved in immune responses and inflammation. Further investigation revealed that (P)RR G-ASOs also inhibited (P)RR in macrophages and in enhanced inflammatory responses to exogenous stimuli. Moreover, deleting the (P)RR in macrophages resulted in accelerated atherosclerosis in WTD fed ApoE-/- mice. Conclusion: (P)RR G-ASOs reduced the plasma lipids in atherosclerotic mice due to hepatic (P)RR deficiency. However, augmented pro-inflammatory responses in macrophages due to (P)RR downregulation counteracted the beneficial effects of lowered plasma lipid concentrations on atherosclerosis. Our study demonstrated that hepatic (P)RR and macrophage (P)RR played a counteracting role in atherosclerosis.

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

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

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