Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea; Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea.
Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea; Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea; Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Gyeongnam 50612, Republic of Korea.
Vascul Pharmacol. 2019 Jul-Aug;118-119:106559. doi: 10.1016/j.vph.2019.04.001. Epub 2019 Apr 4.
Receptors for advanced glycation end-product (RAGE) play a pivotal role in the progression of proliferative vascular diseases. However, the precise mechanisms regulating RAGE expression in vascular smooth muscle cells (VSMCs) of the injured vasculatures is unclear. Given the potential importance of 5-lipoxygenase (5-LO) derived mediators in cellular responses mediated by RAGE, this study aimed to evaluate in VSMCs treated with high mobility group box 1 (HMGB1): 1) the RAGE expression; 2) the AGE-induced VSMC proliferation; 3) the role of 5-LO signaling in HMGB1-induced RAGE expression. In cultured human VSMCs stimulated with HMGB1 (100 ng/ml), RAGE mRNA and protein expression were markedly increased along with an increase in AGE-mediated VSMC proliferation. Both of these effects were markedly attenuated in cells pretreated with zileuton (1-10 μM), a 5-LO inhibitor, as well as in cells transfected with 5-LO siRNA, suggesting a potential involvement of 5-LO signaling in HMGB1-mediated RAGE expression in VSMCs. Moreover, 5-LO expression, accompanied by production of leukotrienes was markedly increased in HMGB1-stimulated VSMCs, which was attenuated in cells deficient of TLR2 or RAGE. Taken together, our results suggest that HMGB1-induced increase in 5-LO expression enhances RAGE expression in VSMCs, which stimulates AGE-mediated VSMC proliferation. Thus, the 5-LO-RAGE signaling axis in VSMCs might serve as a potential therapeutic target for vascular remodeling in the injured vasculature.
晚期糖基化终产物受体（RAGE）在增殖性血管疾病的进展中发挥着关键作用。然而，在损伤血管的血管平滑肌细胞（VSMCs）中调节 RAGE 表达的确切机制尚不清楚。鉴于 5-脂氧合酶（5-LO）衍生的介质在 RAGE 介导的细胞反应中的潜在重要性，本研究旨在评估高迁移率族蛋白 B1（HMGB1）处理的 VSMCs 中的以下内容：1）RAGE 表达；2）AGE 诱导的 VSMC 增殖；3）5-LO 信号在 HMGB1 诱导的 RAGE 表达中的作用。在受到 HMGB1（100ng/ml）刺激的培养的人 VSMCs 中，RAGE mRNA 和蛋白表达明显增加，同时 AGE 介导的 VSMC 增殖也增加。这些作用均在先用 zileuton（1-10μM）预处理的细胞中以及在用 5-LO siRNA 转染的细胞中明显减弱，表明 5-LO 信号可能参与 HMGB1 介导的 VSMCs 中的 RAGE 表达。此外，HMGB1 刺激的 VSMCs 中 5-LO 表达增加，伴随着白三烯的产生，而 TLR2 或 RAGE 缺陷的细胞中则减少。总之，我们的结果表明，HMGB1 诱导的 5-LO 表达增加增强了 VSMCs 中的 RAGE 表达，从而刺激了 AGE 介导的 VSMC 增殖。因此，VSMCs 中的 5-LO-RAGE 信号轴可能成为损伤血管中血管重塑的潜在治疗靶标。
