Trichostatin A, an HDAC Class I/II, Inhibitor, Promotes Pi-Induced Vascular Calcification Via Up-Regulation of the Expression of Alkaline Phosphatase
Trichostatin A, an HDAC Class I/II, Inhibitor, Promotes Pi-Induced Vascular Calcification Via Up-Regulation of the Expression of Alkaline Phosphatase
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DOI：
10.5551/jat.15826
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发表时间：
2013-01-01
影响因子：
4.4
通讯作者：
Wachi, Hiroshi
中科院分区：
文献类型：
--
作者：
Azechi, Takuya;Kanehira, Dan;Wachi, Hiroshi
目的：血管钙化是慢性肾脏病（CKD）的主要并发症，是指血管平滑肌细胞（VSMC）的矿化，由成骨细胞样细胞的表型变化引起。组蛋白去乙酰化酶抑制剂（HDIs）是CKD的潜在治疗药物，已知可促进成骨细胞的分化和矿化。在这项研究中，我们的目的是确定的HDI对VSMCs的表型变化和血管calciferation.Methods的发展的影响：阿司他丁A（TSA），HDI，对人主动脉平滑肌细胞（HASMCs）的影响进行了测定。无机磷（Pi）诱导HASMCs矿化，并通过定量Ca水平和von Kossa染色证实。此外，我们研究了使用siRNA抑制碱性磷酸酶（ALP）的影响，在存在或不存在的TSA.Results：TSA增加的表达和活性的ALP在HASMCs的浓度，这表明组蛋白去乙酰化酶（HDAC）活性的抑制作用，但不对细胞活力。TSA对Pi诱导的HASMCs矿化有促进作用。此外，磷酸钠依赖性磷酸转运蛋白抑制剂膦甲酸（PFA）和siRNA抑制ALP表达均显著抑制TSA促进的HASMCs.Conclusion：这些数据表明，抑制HDAC活性通过上调ALP表达促进Pi诱导的血管钙化。总之，HDIs可能增加CKD患者血管钙化的风险。
Aim: Vascular calcification, a major complication of chronic kidney disease (CKD), refers to the mineralization of vascular smooth muscle cells (VSMCs), resulting from a phenotypic change towards osteoblast-like cells. Histone deacetylase inhibitors (HDIs), potential therapeutic agents for CKD, are known to promote the differentiation and mineralization of osteoblasts. In this study, we aimed to determine the effects of an HDI on the phenotypic change of VSMCs and the development of vascular calcification.Methods: The effect of trichostatin A (TSA), an HDI, on human aortic smooth muscle cells (HASMCs) was determined. The mineralization of HASMCs was induced by inorganic phosphorus (Pi), and was confirmed by quantitation of Ca levels and by von Kossa staining. Furthermore, we examined the effect of alkaline phosphatase (ALP) suppression using siRNA on Pi-induced vascular calcification in the presence or absence of TSA.Results: TSA increased the expression and activity of ALP in HASMCs at a concentration which showed an inhibitory effect of histone deacetylase (HDAC) activity but not on cell viability. Moreover, TSA promoted the Pi-induced mineralization of HASMCs. In addition, both phosphonoformic acid (PFA), which is a sodium-dependent phosphate transporter inhibitor, and suppression of ALP expression by siRNA markedly inhibited the TSA-promoted mineralization of HASMCs.Conclusion: These data show that inhibition of HDAC activity promotes Pi-induced vascular calcification via the up-regulation of ALP expression. Taken together, HDIs may increase the risk of vascular calcification in CKD patients.