Mazière C, Conte M A, Mazière J C
Laboratoire de Biochimie, Université de Picardie Jules Verne, Amiens, France.
Free Radic Biol Med. 2001 Dec 1;31(11):1334-40. doi: 10.1016/s0891-5849(01)00649-9.
Atherosclerosis includes a series of cellular and molecular responses characteristic of an inflammatory disease. We provide evidence that cupric-ion-oxidized LDL (CuLDL) or endothelial cell-oxidized LDL (ELDL) induced the activation by Tyr-phosphorylation of JAK2, one of the Janus kinase involved upstream of STATs in the JAK/STAT pathway of cytokine transduction. Oxidized LDL (OxLDL) also initiated STAT1 and STAT3 Tyr-phosphorylation and translocation to the nucleus, with a more marked effect for the extensively modified CuLDL. Genistein, a nonspecific Tyr-kinase inhibitor, and AG490, a specific inhibitor of JAKs, markedly prevented the CuLDL-induced enhancement of STAT1 and STAT3 Tyr-phosphorylation and DNA-binding activity, suggesting that JAKs are the main kinases involved in STATs' activation by oxidized LDL. In addition, the lipid extract of CuLDL increased the intracellular levels of lipid peroxidation products and the Tyr-phosphorylation of JAK2, STAT1, and STAT3, whereas the antioxidant vitamin E prevented all these effects. These results demonstrate that OxLDL induces the activation by Tyr-phosphorylation of JAK2, STAT1, and STAT3 by generation of an intracellular oxidative stress by means of its lipid peroxidation products, and thus include JAK2 within the range of oxidative stress-activated kinases.
动脉粥样硬化包括一系列具有炎症性疾病特征的细胞和分子反应。我们提供的证据表明，铜离子氧化的低密度脂蛋白（CuLDL）或内皮细胞氧化的低密度脂蛋白（ELDL）通过酪氨酸磷酸化诱导JAK2激活，JAK2是细胞因子转导的JAK/STAT途径中STATs上游的一种Janus激酶。氧化型低密度脂蛋白（OxLDL）也启动了STAT1和STAT3的酪氨酸磷酸化并使其易位至细胞核，对广泛修饰的CuLDL的作用更为显著。染料木黄酮，一种非特异性酪氨酸激酶抑制剂，以及AG490，一种JAKs的特异性抑制剂，显著抑制了CuLDL诱导的STAT1和STAT3酪氨酸磷酸化增强及DNA结合活性，表明JAKs是氧化型低密度脂蛋白激活STATs的主要激酶。此外，CuLDL的脂质提取物增加了细胞内脂质过氧化产物的水平以及JAK2、STAT1和STAT3的酪氨酸磷酸化，而抗氧化剂维生素E可阻止所有这些效应。这些结果表明，OxLDL通过其脂质过氧化产物产生细胞内氧化应激，从而通过酪氨酸磷酸化诱导JAK2、STAT1和STAT3激活，因此将JAK2纳入氧化应激激活激酶的范围内。
