Ceramide mediates Ox-LDL-induced human vascular smooth muscle cell calcification via p38 mitogen-activated protein kinase signaling.
Ceramide mediates Ox-LDL-induced human vascular smooth muscle cell calcification via p38 mitogen-activated protein kinase signaling.
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DOI：
10.1371/journal.pone.0082379
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Liao L;Zhou Q;Song Y;Wu W;Yu H;Wang S;Chen Y;Ye M;Lu L
血管钙化与显著的心血管发病率和死亡率相关，并已被证明是一个类似于骨形成的积极调节过程。氧化低密度脂蛋白（Ox-LDL）已被确定为参与血管平滑肌细胞（vsmc）钙化的调节因子。此外，重组人中性鞘磷脂酶（N-SMase）的过表达已被证明可刺激VSMC凋亡，这在血管钙化的进展中起重要作用。本研究旨在探讨神经酰胺是否通过激活p38丝裂原活化蛋白激酶（MAPK）途径调控ox - ldl诱导的VSMCs钙化。Ox-LDL可提高培养VSMCs的N-SMase活性和神经酰胺水平。在Ox-LDL存在的情况下，N-SMase抑制剂GW4869可降低钙化和成骨转录因子Msx2 mRNA的表达。GW4869可抑制ox - ldl诱导的VSMCs细胞凋亡，而这一作用可被c2 -神经酰胺逆转。此外，c2 -神经酰胺治疗加速VSMC钙化，同时增加ALP活性。此外，c2 -神经酰胺处理增强了ox - ldl诱导的VSMC钙化。添加caspase抑制剂zvd -fmk可减弱ox - ldl诱导的钙化。Ox-LDL和c2 -神经酰胺处理均增加p38 MAPK的磷酸化。SB203580抑制p38 MAPK可减弱ox - ldl诱导的VSMCs钙化。这些数据表明，Ox-LDL激活n - smase -神经酰胺信号通路，刺激p38 MAPK磷酸化，导致VSMC细胞凋亡，引发VSMC钙化。
Vascular calcification is associated with significant cardiovascular morbidity and mortality, and has been demonstrated as an actively regulated process resembling bone formation. Oxidized low density lipoprotein (Ox-LDL) has been identified as a regulatory factor involved in calcification of vascular smooth muscle cells (VSMCs). Additionally, over-expression of recombinant human neutral sphingomyelinase (N-SMase) has been shown to stimulate VSMC apoptosis, which plays an important role in the progression of vascular calcification. The aim of this study is to investigate whether ceramide regulates Ox-LDL-induced calcification of VSMCs via activation of p38 mitogen-activated protein kinase (MAPK) pathway. Ox-LDL increased the activity of N-SMase and the level of ceramide in cultured VSMCs. Calcification and the osteogenic transcription factor, Msx2 mRNA expression were reduced by N-SMase inhibitor, GW4869 in the presence of Ox-LDL. Usage of GW4869 inhibited Ox-LDL-induced apoptosis in VSMCs, an effect which was reversed by C2-ceramide. Additionally, C2-ceramide treatment accelerated VSMC calcification, with a concomitant increase in ALP activity. Furthermore, C2-ceramide treatment enhanced Ox-LDL-induced VSMC calcification. Addition of caspase inhibitor, ZVAD-fmk attenuated Ox-LDL-induced calcification. Both Ox-LDL and C2-ceramide treatment increased the phosphorylation of p38 MAPK. Inhibition of p38 MAPK by SB203580 attenuated Ox-LDL-induced calcification of VSMCs. These data suggest that Ox-LDL activates N-SMase-ceramide signaling pathway, and stimulates phosphorylation of p38 MAPK, leading to apoptosis in VSMCs, which initiates VSMC calcification.
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影响因子：
37.3
作者：
Mondal S;Mandal C;Sangwan R;Chandra S;Mandal C
通讯作者：
Mandal C
影响因子：
3.7
作者：
Kageyama A;Matsui H;Ohta M;Sambuichi K;Kawano H;Notsu T;Imada K;Yokoyama T;Kurabayashi M
通讯作者：
Kurabayashi M
影响因子：
4.8
作者：
Auge, N;Andrieu, N;Salvayre, R
通讯作者：
Salvayre, R
影响因子：
3.1
作者：
Liu, Yiwen;Shanahan, Catherine M.
通讯作者：
Shanahan, Catherine M.
影响因子：
20.1
作者：
Fadini, Gian Paolo;Albiero, Mattia;Avogaro, Angelo
通讯作者：
Avogaro, Angelo