Fetuin-A protects against atherosclerotic calcification in CKD.
Fetuin-A protects against atherosclerotic calcification in CKD.
复制标题
DOI：
10.1681/asn.2008060572
复制
发表时间：
2009-06
期刊：
影响因子：
--
通讯作者：
R. Westenfeld;C. Schäfer;Thilo Krüger;Christian Haarmann;L. Schurgers;C. Reutelingsperger;O. Ivanovski;T. Drueke;Z. Massy;M. Ketteler;J. Floege;W. Jahnen-Dechent
中科院分区：
文献类型：
--
作者：
R. Westenfeld;C. Schäfer;Thilo Krüger;Christian Haarmann;L. Schurgers;C. Reutelingsperger;O. Ivanovski;T. Drueke;Z. Massy;M. Ketteler;J. Floege;W. Jahnen-Dechent
血清钙化抑制剂胎球蛋白A水平降低与透析患者心血管死亡率增加相关。胎球蛋白-A缺陷小鼠显示各种组织的钙化，但血管系统明显没有钙化。这种血管钙化的缺失可能是由于保护了完整的内皮，这在动脉粥样硬化的情况下变得严重受损。为了验证这一假设，我们产生了胎球蛋白A/载脂蛋白E（ApoE）缺陷小鼠，并将其与ApoE缺陷和野生型小鼠的动脉粥样硬化形成和骨外钙化进行了比较。我们将小鼠分为三个治疗组，持续9周：（1）标准饮食，（2）高磷酸盐饮食，或（3）单侧肾切除术（导致慢性肾病[CKD]）加高磷酸盐饮食。血清尿素、磷酸盐和甲状旁腺激素水平在所有基因型干预后相似。胎球蛋白-A缺乏并不影响ApoE缺乏时观察到的主动脉脂质沉积、新生内膜形成和冠状动脉硬化的程度，但胎球蛋白-A缺乏、高磷血症和CKD的组合导致该动脉粥样硬化模型中血管钙化增加15倍。胎球蛋白A缺乏几乎只促进动脉粥样硬化病变的内膜钙化，而不是中膜钙化。高磷酸盐饮食和CKD也导致瓣膜钙化和与瓣膜相关的凋亡增加，野生型小鼠最少，ApoE缺陷型小鼠居中，胎球蛋白A/ApoE缺陷型小鼠最多。此外，在ApoE缺陷小鼠中，胎球蛋白A缺乏、高磷酸盐饮食和CKD的组合大大增强了心肌钙化，而胎球蛋白A缺乏并不影响肾钙化的发生率。总之，胎球蛋白-A抑制软组织和脉管系统中的病理性钙化，即使在动脉粥样硬化的情况下。
Reduced serum levels of the calcification inhibitor fetuin-A associate with increased cardiovascular mortality in dialysis patients. Fetuin-A-deficient mice display calcification of various tissues but notably not of the vasculature. This absence of vascular calcification may result from the protection of an intact endothelium, which becomes severely compromised in the setting of atherosclerosis. To test this hypothesis, we generated fetuin-A/apolipoprotein E (ApoE)-deficient mice and compared them with ApoE-deficient and wild-type mice with regard to atheroma formation and extraosseous calcification. We assigned mice to three treatment groups for 9 wk: (1) Standard diet, (2) high-phosphate diet, or (3) unilateral nephrectomy (causing chronic kidney disease [CKD]) plus high-phosphate diet. Serum urea, phosphate, and parathyroid hormone levels were similar in all genotypes after the interventions. Fetuin-A deficiency did not affect the extent of aortic lipid deposition, neointima formation, and coronary sclerosis observed with ApoE deficiency, but the combination of fetuin-A deficiency, hyperphosphatemia, and CKD led to a 15-fold increase in vascular calcification in this model of atherosclerosis. Fetuin-A deficiency almost exclusively promoted intimal rather than medial calcification of atheromatous lesions. High-phosphate diet and CKD also led to an increase in valvular calcification and aorta-associated apoptosis, with wild-type mice having the least, ApoE-deficient mice intermediate, and fetuin-A/ApoE-deficient mice the most. In addition, the combination of fetuin-A deficiency, high-phosphate diet, and CKD in ApoE-deficient mice greatly enhanced myocardial calcification, whereas the absence of fetuin-A did not affect the incidence of renal calcification. In conclusion, fetuin-A inhibits pathologic calcification in both the soft tissue and vasculature, even in the setting of atherosclerosis.