Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
Sci Rep. 2018 Feb 21;8(1):3377. doi: 10.1038/s41598-017-17540-6.
Vascular calcification is a pathologic response to mineral imbalances and is prevalent in atherosclerosis, diabetes mellitus, and chronic kidney disease. When located in the media, it is highly associated with increased cardiovascular morbidity and mortality, particularly in patients on dialysis. Vascular calcification is tightly regulated and controlled by a series of endogenous factors. In the present study, we assess the effects of lysosomal and endosomal inhibition on calcification in vascular smooth muscle cells (VSMCs) and aortic rings. We observed that lysosomal function was increased in VSMCs cultured in calcification medium containing 3.5 mM inorganic phosphate (Pi) and 3 mM calcium (Ca) for 7 days. We also found that the lysosomal marker lysosome-associated membrane protein 2 was markedly increased and colocalized with osteogenic markers in calcified aortas from vitamin D-treated rats. Interestingly, both the lysosomal inhibitor chloroquine and the endosomal inhibitor dynasore dose-dependently enhanced Pi + Ca-mediated VSMC calcification. Inhibition of lysosomal and endosomal function also promoted osteogenic transformation of VSMCs. Additionally, lysosome inhibition increased Pi-induced medial calcification of aortic rings ex vivo. These data suggest that the endosome-lysosome system may play a protective role in VSMC and medial artery calcification.
血管钙化是矿物质失衡的病理反应，常见于动脉粥样硬化、糖尿病和慢性肾脏病。当位于中膜时，它与心血管发病率和死亡率的增加高度相关，特别是在透析患者中。血管钙化受到一系列内源性因素的紧密调节和控制。在本研究中，我们评估了溶酶体和内体抑制对血管平滑肌细胞 (VSMC) 和主动脉环钙化的影响。我们观察到，在含有 3.5 mM 无机磷酸盐 (Pi) 和 3 mM 钙 (Ca) 的钙化培养基中培养 7 天的 VSMC 中，溶酶体功能增加。我们还发现，溶酶体标记物溶酶体相关膜蛋白 2在维生素 D 处理的大鼠钙化主动脉中明显增加，并与成骨标志物共定位。有趣的是，溶酶体抑制剂氯喹和内体抑制剂 dynasore 均以剂量依赖性方式增强了 Pi+Ca 介导的 VSMC 钙化。溶酶体和内体功能的抑制也促进了 VSMC 的成骨转化。此外，溶酶体抑制增加了 Pi 诱导的离体主动脉环中膜的钙化。这些数据表明，内体-溶酶体系统可能在 VSMC 和中膜动脉钙化中起保护作用。
