Kawahara Ko-Ichi, Hashiguchi Teruto, Kikuchi Kiyoshi, Tancharoen Salunya, Miura Naoki, Ito Takashi, Oyama Yoko, Nawa Yuko, Biswas Kamal K, Meng Xiaojie, Morimoto Yoko, Shrestha Binita, Sameshima Hisayo, Maruyama Ikuro
Department of Laboratory and Vascular Medicine, Cardiovascular and Respiratory Disorders, Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan.
Int J Mol Med. 2008 Nov;22(5):639-44.
High mobility group box 1 (HMGB1) is a non-histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis. The HMGB1 functions as a potent proinflammatory cytokine in the extracellular spaces. Recently, HMGB1 has been implicated in the progression of atherosclerosis. However, the association between HMGB1 and the development of atherosclerosis is poorly understood. Therefore, we examined whether serotonin (5-HT), a key factor involved in the development of atherosclerosis, induced HMGB1 release in human umbilical vein endothelial cells (HUVECs). We found that 5-HT induced the release of HMGB1 but not of ERK1/2 and JNK from HUVECs via the 5-HT receptor (5-HT1B)/p38 mitogen-activated protein kinase (MAPK) signaling pathway. The p38MAPK inhibitor SB203580 and the 5-HT1B antagonist GR55526 markedly inhibited HMGB1 release from 5-HT-stimulated HUVECs. The vascular endothelial growth factor (VEGF) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis. We found that HMGB1 induced VEGF production in macrophage-like RAW264.7 cells. HMGB1 induced the activation of p38MAPK, ERK1/2 and Akt. The PI3-kinase inhibitor LY294002 significantly inhibited VEGF production in HMGB1-stimulated macrophages, while other kinase inhibitors did not. These results suggest that HMGB1 release may contribute as a risk factor in the development and progression of atherosclerosis.
高迁移率族蛋白B1（HMGB1）是一种非组蛋白核蛋白，在诸如内毒素或坏死等刺激下，它会从活化巨噬细胞的细胞核释放到细胞外空间。HMGB1在细胞外空间中作为一种强效促炎细胞因子发挥作用。最近，HMGB1与动脉粥样硬化的进展有关。然而，HMGB1与动脉粥样硬化发生之间的关联仍知之甚少。因此，我们研究了血清素（5-羟色胺，5-HT）这种参与动脉粥样硬化发生的关键因素是否会诱导人脐静脉内皮细胞（HUVECs）释放HMGB1。我们发现5-HT通过5-HT受体（5-HT1B）/p38丝裂原活化蛋白激酶（MAPK）信号通路诱导HUVECs释放HMGB1，但不诱导ERK1/2和JNK释放。p38MAPK抑制剂SB203580和5-HT1B拮抗剂GR55526显著抑制5-HT刺激的HUVECs释放HMGB1。动脉粥样硬化病变中活化巨噬细胞衍生的血管内皮生长因子（VEGF）在动脉粥样硬化进展中也起重要作用。我们发现HMGB1诱导巨噬细胞样RAW264.7细胞产生VEGF。HMGB1诱导p38MAPK、ERK1/2和Akt活化。PI3激酶抑制剂LY294002显著抑制HMGB1刺激的巨噬细胞产生VEGF，而其他激酶抑制剂则无此作用。这些结果表明，HMGB1的释放可能是动脉粥样硬化发生和进展的一个危险因素。
