Dragomir Elena, Manduteanu Ileana, Calin Manuela, Gan Ana Maria, Stan Daniela, Koenen Rory Ryan, Weber Christian, Simionescu Maya
Institute of Cellular Biology and Pathology Nicolae Simionescu, BP Hasdeu Street, PO Box 35-14, 79691-Bucharest, Romania.
Thromb Haemost. 2008 Dec;100(6):1155-65.
The major complication of diabetes mellitus is accelerated atherosclerosis that entails an inflammatory process, in which fractalkine and monocyte chemotactic protein-1 (MCP-1) play a key role. We investigated the effect of diabetes-associated high glucose (HG) on these chemokines and signalling mechanisms involved in human aortic smooth muscle cells (SMC). Exposure of SMC to HG resulted in an increase of fractalkine and MCP-1 expression and the activated mitogen-activated protein kinase (MAPK) signalling pathway, a process associated with elevated oxidative stress. Transfection with decoy oligodeoxynucleotides identified the involvement of transcription factors activator protein 1 (AP-1) and nuclear factor kappa B (NF-kappaB) in the observed up-regulation of chemokines. The MAPK inhibitors blocked the phosphorylation of IkBalpha and c-jun, indicating the role of MAPK in NF-kappaB and AP-1 activation in SMC under HG conditions. The up-regulation of MCP-1 and fractalkine was associated with increased adhesive interactions between HG-exposed SMC and monocytes. Treatment of HG-exposed SMC with peroxisome proliferator-activated receptors alpha (PPARalpha) activators (fenofibrate and clofibrate) resulted in a reduction of mRNA and protein expression of MCP-1 and fractalkine. In conclusion, HG upregulates the expression of fractalkine and MCP-1 in SMC leading to increased monocyte-SMC adhesive interactions by a mechanism involving activation of MAPK, activator protein-1 (AP-1) and NF-kappaB. The increased expression of these two pro-inflammatory chemokines and the ensuing increased adhesion between SMC and monocytes may trigger the inflammatory process associated with further vascular complications of diabetes.
糖尿病的主要并发症是加速动脉粥样硬化，这需要一个炎症过程，其中趋化因子和单核细胞趋化蛋白-1（MCP-1）起关键作用。我们研究了糖尿病相关的高血糖（HG）对这些趋化因子以及人主动脉平滑肌细胞（SMC）中涉及的信号传导机制的影响。将SMC暴露于HG会导致趋化因子和MCP-1表达增加以及丝裂原活化蛋白激酶（MAPK）信号通路激活，这一过程与氧化应激升高相关。用诱饵寡脱氧核苷酸转染确定了转录因子激活蛋白1（AP-1）和核因子κB（NF-κB）参与了观察到的趋化因子上调。MAPK抑制剂阻断了IkBα和c-jun的磷酸化，表明在HG条件下MAPK在SMC中NF-κB和AP-1激活中的作用。MCP-1和趋化因子的上调与暴露于HG的SMC和单核细胞之间的黏附相互作用增加有关。用过氧化物酶体增殖物激活受体α（PPARα）激活剂（非诺贝特和氯贝丁酯）处理暴露于HG的SMC会导致MCP-1和趋化因子的mRNA和蛋白表达降低。总之，HG上调了SMC中趋化因子和MCP-1的表达，通过涉及MAPK、激活蛋白-1（AP-1）和NF-κB激活的机制导致单核细胞-SMC黏附相互作用增加。这两种促炎趋化因子表达的增加以及随之而来的SMC和单核细胞之间黏附的增加可能引发与糖尿病进一步血管并发症相关的炎症过程。
