High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells
High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells
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DOI：
10.1093/ndt/gfl429
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发表时间：
2006-12-01
影响因子：
6.1
通讯作者：
Moe, Sharon M.
中科院分区：
文献类型：
--
作者：
Chen, Neal X.;Duan, Danxia;Moe, Sharon M.
背景。血管钙化在糖尿病中很常见，但其发病机制尚不清楚。为了研究其发病机制，我们首先检查了接受肾移植的糖尿病和非糖尿病患者的腹壁下动脉的组织学。为了研究高血糖的作用，将牛血管平滑肌细胞（BVSMCs）与正常（5 mM）或高糖（25 mM）孵育48或72小时。结果表明，与非糖尿病患者相比，糖尿病患者的骨基质蛋白骨桥蛋白、I型胶原蛋白、骨唾液蛋白和碱性磷酸酶（ALP）的表达明显增加，骨质钙化程度更大。体外研究表明，高糖可使成骨细胞转录因子核心结合因子α亚基1 （Cbfa1）及其下游蛋白骨钙素的表达分别提高1.9倍和1.8倍，ALP活性提高1.5倍。在蛋白激酶c抑制剂的存在下，这些发现被削弱了。高葡萄糖也以时间依赖性的方式显著增强了BVSMC的钙化（2.20 +/- 0.50 vs 1.35 +/- 0.55 mu mol/mg，第7天；5.04 +/- 1.35 vs 3.12 +/- 0.92 mu mol/mg，第14天；P < 0.05）。高糖还诱导骨形态发生蛋白-2（一种已知的骨诱导因子）的分泌，并在第7天和第14天进一步增加钙化过程中正常的分泌，分别增加43%和57%。这些结果表明，糖尿病患者的血管钙化是一个细胞介导的过程，其特征是VSMCs向成骨细胞样细胞的表型变化，骨基质蛋白表达增加，高血糖可能直接诱导这些变化。
Background. Vascular calcification is common in diabetes but the pathogenesis is poorly understood.Methods. To investigate the pathogenesis, we first examined the histology of inferior epigastric arteries from diabetic and non-diabetic patients undergoing a renal transplant. To examine the role of hyperglycaemia, bovine vascular smooth muscle cells (BVSMCs) were incubated with normal (5 mM) or high glucose (25 mM) for 48 or 72 h.Results. The results demonstrated that diabetic patients, compared with non-diabetic patients, had significantly greater calcification and increased expression of the bone matrix proteins osteopontin, type I collagen, bone sialoprotein and alkaline phosphatase (ALP). The in vitro studies demonstrated that high glucose increased the expression of the osteoblast transcription factor core binding factor alpha subunit 1 (Cbfa1) and its downstream protein osteocalcin by 1.9-fold and 1.8-fold, respectively, and ALP activity by 1.5-fold. These findings were blunted in the presence of an inhibitor to protein kinase C. High glucose also significantly enhanced calcification in BVSMC in a time-dependent manner (2.20 +/- 0.50 vs 1.35 +/- 0.55 mu mol/mg, day 7; 5.04 +/- 1.35 vs 3.12 +/- 0.92 mu mol/mg, day 14; P < 0.05). High glucose also induced the secretion of bone morphogenetic protein-2, a known osteoinductive factor, and further increased the secretion normally seen during calcification by 43% at day 7 and 57% at day 14.Conclusions. These results demonstrate that vascular calcification in patients with diabetes is a cell-mediated process characterized by a phenotypic change of VSMCs to osteoblast-like cells with increased bone matrix protein expression, and that hyperglycaemia may directly induce these changes.