Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro
Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro
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DOI：
10.1111/j.1523-1755.2004.66015.x
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发表时间：
2004-12-01
影响因子：
19.6
通讯作者：
Giachelli, CM
中科院分区：
文献类型：
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作者：
Yang, H;Curinga, G;Giachelli, CM
背景高磷血症、钙磷乘积（Ca x P）升高和钙负荷是血管钙化的主要原因，与透析患者心血管发病率和死亡率的增加相关。为了解决这些发现的潜在机制，我们利用了体外人平滑肌细胞（HSMC）血管钙化模型。先前使用该系统的研究表明，在高磷酸盐血症范围内用磷水平处理的HSMC培养物的钙化增强，并且在这种作用中涉及钠依赖性磷酸盐共转运依赖性机制。在本研究中，我们研究了体外增加钙浓度对HSMC钙化的影响。在正常磷条件下，增加钙到高钙血症个体中观察到的水平增加了HSMC培养物的矿化。重要的是，在这些总钙浓度下，离子钙水平从1.2 mmol/L增加到1.7 mmol/L，分别与正常钙血症和高钙血症个体的生理学水平一致。此外，增加钙和磷水平导致加速和增加矿化的文化。钙诱导的矿化依赖于钠依赖性磷酸盐协同转运蛋白的功能，因为它被膦甲酸（PFA）抑制。虽然高钙并不影响短期磷转运动力学，但长期高钙处理可诱导钠依赖性磷酸盐协同转运蛋白Pit-1的表达。这些研究表明，高钙可能会刺激HSMC矿化，通过提高钙磷乘积和增强钠依赖性磷酸盐协同转运蛋白依赖性矿化途径先前观察到的HSMCs。
Background. Hyperphosphatemia, elevated calcium x phosphorus product (Ca x P), and calcium burden, major causes of vascular calcification, are correlated with increased cardiovascular morbidity and mortality in dialysis patients.Methods. To address the underlying mechanisms responsible for these findings, we have utilized an in vitro human smooth muscle cell (HSMC) model of vascular calcification. Previous studies using this system demonstrated enhanced calcification of HSMC cultures treated with phosphorus levels in the hyperphosphatemic range, and implicated a sodium-dependent phosphate cotransport-dependent mechanism in this effect. In the present study, we examine the effect of increasing calcium concentrations on HSMC calcification in vitro.Results. Increasing calcium to levels observed in hypercalcemic individuals increased mineralization of HSMC cultures under normal phosphorus conditions. Importantly, at these total calcium concentrations, ionized calcium levels increased from 1.2 mmol/L to 1.7 mmol/L, consistent with levels observed physiologically in normocalcemic and hypercalcemic individuals, respectively. Furthermore, increasing both calcium and phosphorus levels led to accelerated and increased mineralization in the cultures. Calcium-induced mineralization was dependent on the function of a sodium-dependent phosphate cotransporter, since it was inhibited by phosphonoformic acid (PFA). While elevated calcium did not affect short-term phosphorus transport kinetics, long-term elevated calcium treatment of HSMCs induced expression of the sodium-dependent phosphate cotransporter, Pit-1.Conclusion. These studies suggest that elevated calcium may stimulate HSMC mineralization by elevating Ca x P product and enhancing the sodium-dependent phosphate cotransporter-dependent mineralization pathway previously observed in HSMCs.