End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles.
End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles.
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末期肾脏疾病诱导的高钙血症可能通过膜毒素VI富集瓣膜间质细胞衍生的矩阵囊泡来促进主动脉瓣钙化。
DOI：
10.1002/jcp.25935
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发表时间：
2017-11
影响因子：
5.6
通讯作者：
Macrae VE
中科院分区：
文献类型：
--
作者：
Cui L;Rashdan NA;Zhu D;Milne EM;Ajuh P;Milne G;Helfrich MH;Lim K;Prasad S;Lerman DA;Vesey AT;Dweck MR;Jenkins WS;Newby DE;Farquharson C;Macrae VE
终末期肾病 (ESRD) 患者的循环钙 (Ca) 和磷酸盐 (Pi) 升高，并且钙化性主动脉瓣疾病 (CAVD) 进展加速。我们假设基质囊泡 (MV) 启动 CAVD 的钙化过程。 Ca 在 4.5 mM 时诱导大鼠瓣膜间质细胞 (VIC) 钙化（16.4 倍；p<0.05），而单独使用 Pi 治疗则没有效果。 Ca (2.7mM) 和 Pi (2.5mM) 协同诱导 VIC 中的钙沉积（10.8 倍；p<0.001）。 Ca 处理增加了成骨标志物 Msx2、Runx2 和 Alpl 的 mRNA (p<<0.01)。通过超速离心从用对照或钙化培养基（含有2.7mM Ca和2.5mM Pi）培养16小时的VIC中收获MV。蛋白质组学分析揭示了外泌体蛋白的显着富集，包括 CD9、CD63、LAMP-1 和 LAMP-2，以及钙结合蛋白膜联蛋白家族的随之上调。特别值得注意的是，Annexin VI 在钙化 VIC 衍生的 MV 中富集（51.9 倍；p<0.05）。通过使用 Ingenuity Pathway Analysis (IPA) 的生物信息学分析，在钙化 VIC 衍生的 MV 中发现了与心血管功能相关的经典信号通路的上调，包括醛固酮、Rho 激酶和金属结合。使用人钙化瓣膜组织的进一步研究通过透射电子显微镜 (TEM) 揭示了膜联蛋白 VI 与细胞外基质中 MV 区域的共定位。这些发现共同强调了 VIC 衍生的 MV 在 CAVD 中的关键作用。此外，我们认为钙是主动脉瓣钙化的关键驱动因素，这可能直接导致 ESRD 患者加速 CAVD 发展的易感性增加。
Patients with end‐stage renal disease (ESRD) have elevated circulating calcium (Ca) and phosphate (Pi), and exhibit accelerated progression of calcific aortic valve disease (CAVD). We hypothesized that matrix vesicles (MVs) initiate the calcification process in CAVD. Ca induced rat valve interstitial cells (VICs) calcification at 4.5 mM (16.4‐fold; p < 0.05) whereas Pi treatment alone had no effect. Ca (2.7 mM) and Pi (2.5 mM) synergistically induced calcium deposition (10.8‐fold; p < 0.001) in VICs. Ca treatment increased the mRNA of the osteogenic markers Msx2, Runx2, and Alpl (p < 0.01). MVs were harvested by ultracentrifugation from VICs cultured with control or calcification media (containing 2.7 mM Ca and 2.5 mM Pi) for 16 hr. Proteomics analysis revealed the marked enrichment of exosomal proteins, including CD9, CD63, LAMP‐1, and LAMP‐2 and a concomitant up‐regulation of the Annexin family of calcium‐binding proteins. Of particular note Annexin VI was shown to be enriched in calcifying VIC‐derived MVs (51.9‐fold; p < 0.05). Through bioinformatic analysis using Ingenuity Pathway Analysis (IPA), the up‐regulation of canonical signaling pathways relevant to cardiovascular function were identified in calcifying VIC‐derived MVs, including aldosterone, Rho kinase, and metal binding. Further studies using human calcified valve tissue revealed the co‐localization of Annexin VI with areas of MVs in the extracellular matrix by transmission electron microscopy (TEM). Together these findings highlight a critical role for VIC‐derived MVs in CAVD. Furthermore, we identify calcium as a key driver of aortic valve calcification, which may directly underpin the increased susceptibility of ESRD patients to accelerated development of CAVD.
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