Department of Calcified Tissue Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Neuroprotection Research Laboratories, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth Street, Charlestown, MA 02129, USA.
J Biochem. 2024 May 31;175(6):643-648. doi: 10.1093/jb/mvae011.
Vascular calcification, a major risk factor for cardiovascular events, is associated with a poor prognosis in chronic kidney disease (CKD) patients. This process is often associated with the transformation of vascular smooth muscle cells (VSMCs) into cells with osteoblast-like characteristics. Damage-associated molecular patterns (DAMPs), such as extracellular histones released from damaged or dying cells, are suspected to accumulate at calcification sites. To investigate the potential involvement of DAMPs in vascular calcification, we assessed the impact of externally added histones (extracellular histones) on calcium and inorganic phosphate-induced calcification in mouse VSMCs. Our study found that extracellular histones intensified calcification. We also observed that the histones decreased the expression of VSMC marker genes while simultaneously increasing the expression of osteoblast marker genes. Additionally, histones treated with DNase I, which degrades dsDNA, attenuated this calcification, compared with the non-treated histones, suggesting a potential involvement of dsDNA in this process. Elevated levels of dsDNA were also detected in the serum of CKD model mice, underlining its potential role in vascular calcification in CKD. Our findings suggest that extracellular histones could play a pivotal role in the vascular calcification observed in CKD.
血管钙化是心血管事件的一个主要危险因素，与慢性肾脏病（CKD）患者的预后不良有关。这个过程通常与血管平滑肌细胞（VSMCs）向成骨样细胞的转化有关。损伤相关分子模式（DAMPs），如受损或死亡细胞释放的细胞外组蛋白，被怀疑在钙化部位积累。为了研究 DAMPs 在血管钙化中的潜在作用，我们评估了外源性添加的组蛋白（细胞外组蛋白）对钙和无机磷酸盐诱导的小鼠 VSMCs 钙化的影响。我们的研究发现，细胞外组蛋白加剧了钙化。我们还观察到组蛋白降低了 VSMC 标记基因的表达，同时增加了成骨细胞标记基因的表达。此外，用降解双链 DNA 的 DNase I 处理组蛋白，与未处理的组蛋白相比，减弱了这种钙化，这表明 dsDNA 可能参与了这个过程。在 CKD 模型小鼠的血清中也检测到了高水平的 dsDNA，这强调了它在 CKD 血管钙化中的潜在作用。我们的研究结果表明，细胞外组蛋白可能在 CKD 中观察到的血管钙化中起关键作用。
