Farnesoid X receptor activation prevents the development of vascular calcification in ApoE-/- mice with chronic kidney disease.
Farnesoid X receptor activation prevents the development of vascular calcification in ApoE-/- mice with chronic kidney disease.
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DOI：
10.1161/circresaha.109.212969
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发表时间：
2010-06-25
影响因子：
20.1
通讯作者：
Miyazaki M
中科院分区：
文献类型：
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作者：
Miyazaki-Anzai S;Levi M;Kratzer A;Ting TC;Lewis LB;Miyazaki M
血管钙化与心血管发病率和死亡率高度相关，尤其是慢性肾病患者。核受体法尼醇 X 受体 (FXR) 与多种细胞类型中脂质、碳水化合物和胆汁酸代谢的控制有关。尽管最近的研究表明 FXR 也在血管平滑肌细胞中表达，但其在脉管组织中的生理作用仍然不清楚。在这里，我们研究了 FXR 在血管钙化中的作用。 FXR 基因是一种胆汁酸核受体，在牛钙化血管细胞 (CVC) 的成骨分化过程中和在患有慢性肾病的载脂蛋白 E (ApoE)−/− 小鼠的主动脉中被高度诱导，这些小鼠分别是主动脉钙化的常见组织培养物和小鼠模型。合成 FXR 激动剂 6α-乙基鹅去氧胆酸 (INT-747) 激活 FXR，抑制 CVC 中磷酸盐诱导的矿化和甘油三酯积累。 FXR 显性负表达增强了 CVC 的矿化并阻断了 INT-747 的抗钙化作用，而 VP16FXR 是一种组成型活性形式，可减少 CVC 的矿化。 INT-747 治疗还增加了磷酸化 c-Jun N 末端激酶 (JNK)。 SP600125（特异性 JNK 抑制剂）显着诱导 CVC 矿化和 ALP 表达，表明 INT-747 的抗钙化作用是由于 JNK 激活。我们还发现 INT-747 可以改善 5/6 肾切除 ApoE−/− 小鼠中慢性肾病 (CKD) 诱导的血管钙化，而不影响动脉粥样硬化的发展。这些观察结果提供了直接证据，证明 FXR 是调节血管成骨分化的关键信号成分，因此代表了治疗血管钙化的有希望的靶标。
Vascular calcification is highly associated with cardiovascular morbidity and mortality, especially in patients with chronic kidney disease. The nuclear receptor farnesoid X receptor (FXR) has been implicated in the control of lipid, carbohydrate and bile acid metabolism in several cell types. Although recent studies have shown that FXR is also expressed in vascular smooth muscle cells, its physiological role in vasculature tissue remains obscure. Here, we have examined the role of FXR in vascular calcification. The FXR gene, a bile acid nuclear receptor, was highly induced during osteogenic differentiation of bovine calcifying vascular cells (CVC) and in the aorta of apolipoprotein E (ApoE)−/− mice with chronic kidney disease which are common tissue culture and mouse model, respectively, for aortic calcification. FXR activation by a synthetic FXR agonist, 6α-ethyl chenodeoxycholic acid (INT-747) inhibited phosphate induced-mineralization and triglyceride accumulation in CVC. FXR dominant negative expression augmented mineralization of CVC and blocked the anti-calcific effect of INT-747 whereas VP16FXR that is a constitutively active form reduced mineralization of CVC. INT-747 treatment also increased phosphorylated c-Jun N-terminal kinase (JNK). SP600125 (specific JNK inhibitor) significantly induced mineralization of CVC and ALP expression, suggesting that the anti-calcific effect of INT-747 is due to JNK activation. We also found that INT-747 ameliorates chronic kidney disease (CKD) induced-vascular calcification in 5/6 nephrectomized ApoE−/− mice without affecting the development of atherosclerosis. These observations provide direct evidence for that FXR is a key signaling component in regulation of vascular osteogenic differentiation and, thus representing a promising target for the treatment of vascular calcification.