Vascular-directed tissue factor pathway inhibitor overexpression regulates plasma cholesterol and reduces atherosclerotic plaque development.
Vascular-directed tissue factor pathway inhibitor overexpression regulates plasma cholesterol and reduces atherosclerotic plaque development.
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DOI：
10.1161/circresaha.109.195016
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发表时间：
2009-09-25
影响因子：
20.1
通讯作者：
Simari RD
中科院分区：
文献类型：
--
作者：
Pan S;White TA;Witt TA;Chiriac A;Mueske CS;Simari RD
组织因子途径抑制物（TFPI）是组织因子途径的有效调节剂，并在血浆中与脂蛋白结合。为了确定TFPI在动脉粥样硬化发展中的作用，我们饲养了过表达TFPI的小鼠，使其成为载脂蛋白E−/−（apoE）背景。在高脂肪饮食中，与apoE-/-小鼠相比，SM 22 α-TFPI/apoE-/-小鼠的主动脉斑块负荷更少。出乎意料的是，与apoE−/−小鼠相比，SM 22 α-TFPI/apoE−/−小鼠的血浆胆固醇水平较低。此外，喂食高脂肪饲料的SM 22 α-TFPI小鼠的胆固醇水平低于野生型小鼠。由于TFPI与脂蛋白相关，其羧基末端（TFPIct）已被证明是VLDL受体的配体，我们假设TFPI过表达可能调节脂蛋白分布。我们在体外定量了来自SM 22 α-TFPI和野生型小鼠的小鼠主动脉平滑肌细胞（mASMC）中的VLDL结合和摄取。来自SM 22 α-TFPI小鼠的mASMCs显示出比来自野生型小鼠的mASMCs更高的VLDL结合和内化。由于SM 22 α-TFPI小鼠的TFPI抗原循环水平增加，我们研究了TFPIct是否可以改变脂蛋白分布。在体外，TFPIct增加极低密度脂蛋白的结合，摄取和降解小鼠胚胎成纤维细胞。此外，这种作用被肝素酶处理阻断。在体内，全身给予TFPIct可降低apoE−/−小鼠的血浆胆固醇水平。这些研究表明TFPI的过表达通过其羧基末端与脂蛋白和硫酸乙酰肝素蛋白聚糖的相互作用降低血浆胆固醇。
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−/− (apoE) background. On a high fat diet, 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. Since TFPI is associated with lipoproteins and its carboxy terminus (TFPIct) has been shown to be a ligand for the 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 (mASMCs) from SM22α-TFPI and wild type mice. mASMCs from SM22α-TFPI mice demonstrated higher VLDL binding and internalization compared to those from wild type mice. Since 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. These studies suggest that overexpression of TFPI lowers plasma cholesterol through the interaction of its carboxy terminus with lipoproteins and heparan sulfate proteoglycans.