Department of Pharmacology, School of Medicine, Institute of Health Sciences, Medical Research Center for Neural Dysfunction, Biomedical Center (BK21), Gyeongsang National University School of Medicine, Jinju 660-290, Republic of Korea.
Atherosclerosis. 2011 Nov;219(1):57-64. doi: 10.1016/j.atherosclerosis.2011.06.043. Epub 2011 Jun 30.
Activation of the NF-κB and mitogen activated protein (MAP) kinases plays an important role in the expression of inflammatory genes such as adhesion molecules. Although compound C is known as an AMPK inhibitor, AMPK-independent action of it has been recognized. Effects on the expression of ICAM-1 and VCAM-1 by compound C were investigated in TNF-α-activated human umbilical vein endothelial cells (HUVECs) in vitro and in thoracic aorta of rats treated with lipopolysaccharide (LPS) in vivo. Compound C inhibited ICAM-1 and VCAM-1 expression at the transcriptional as well as translational level in TNF-α-activated HUVECs. In both DN-AMPK- and AMPKα(1)-siRNA-transfected HUVECs, compound C still inhibited TNF-α-induced VCAM-1 and ICAM-1 expression, indicating that this is AMPK-independent action. Interestingly, compound C significantly inhibited NF-κB activity and translocation of p65 to nucleus in HUVECs when activated with TNF-α. Importantly, administration of compound C (0.2 mg/kg) significantly reduced expression of both ICAM-1 and VCAM-1 in LPS-treated rat thoracic aortas. In addition, compound C significantly inhibited iNOS and production of NO in both TNF-α- and LPS-activated RAW 264.7 cells. Finally, compound C significantly inhibited phosphorylation of Akt and p-38MAPK but not protein kinase c or ERK1/2 in HUVECs. Taken together, we conclude that adhesion molecules (ICAM-1, VCAM-1) are to be the novel targets of compound C in preventing inflammatory insult to endothelial cells independent of AMPK inhibition via inhibition of NF-κB activity along with inhibition of phosphorylation of PI3K and P38 MAPK.
NF-κB 和丝裂原活化蛋白 (MAP) 激酶的激活在黏附分子等炎症基因的表达中起着重要作用。虽然化合物 C 被认为是 AMPK 抑制剂，但它已被认为具有 AMPK 非依赖性作用。在体外 TNF-α 激活的人脐静脉内皮细胞 (HUVEC) 和体内用脂多糖 (LPS) 处理的大鼠胸主动脉中研究了化合物 C 对 ICAM-1 和 VCAM-1 表达的影响。化合物 C 抑制 TNF-α 激活的 HUVEC 中转录和翻译水平的 ICAM-1 和 VCAM-1 表达。在 DN-AMPK-和 AMPKα(1)-siRNA 转染的 HUVEC 中，化合物 C 仍然抑制 TNF-α 诱导的 VCAM-1 和 ICAM-1 表达，表明这是 AMPK 非依赖性作用。有趣的是，当用 TNF-α 激活时，化合物 C 显著抑制 HUVEC 中的 NF-κB 活性和 p65 向核内易位。重要的是，给予化合物 C（0.2 mg/kg）可显著降低 LPS 处理的大鼠胸主动脉中 ICAM-1 和 VCAM-1 的表达。此外，化合物 C 还可显著抑制 TNF-α 和 LPS 激活的 RAW 264.7 细胞中 iNOS 的产生和 NO 的产生。最后，化合物 C 可显著抑制 HUVEC 中 Akt 和 p-38MAPK 的磷酸化，但不抑制蛋白激酶 C 或 ERK1/2 的磷酸化。总之，我们的结论是，黏附分子（ICAM-1、VCAM-1）是化合物 C 通过抑制 NF-κB 活性以及抑制 PI3K 和 P38 MAPK 的磷酸化，防止内皮细胞炎症损伤的新靶点，与 AMPK 抑制无关。
