Boyle Joseph J, Weissberg Peter L, Bennett Martin R
Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, UK.
Arterioscler Thromb Vasc Biol. 2002 Oct 1;22(10):1624-30. doi: 10.1161/01.atv.0000033517.48444.1a.
We have previously shown that macrophages induce vascular smooth muscle cell (VSMC) apoptosis in vitro by cell-cell proximity and Fas-L/Fas interactions. Because NO is a short-range mediator, we tested whether NO mediates macrophage-induced VSMC apoptosis.
NO synthase (NOS) inhibitors markedly inhibited macrophage-induced apoptosis of carotid plaque VSMCs (apoptotic indices, 81+/-2.9% for control and 28.2+/-3.9% for N(G)-nitro-L-arginine methyl ester [L-NAME] treatment) and coronary medial VSMCs (apoptotic indices, 76+/-5.5% for control and 3.5+/-0.8% for L-NAME treatment). Inactive enantiomers were without effect (P>0.05). Cultured macrophages, but not VSMCs, expressed inducible NOS (but not neuronal NOS or endothelial NOS) concomitant with activation and secreted 1.51+/-0.3 fmol nitrite per cell, which was blocked by L-NAME (100 micro mol/L). Diethylene triamine nitric oxide (DETA/NO) and sodium nitroprusside (NO donors) induced VSMC cell-surface Fas and enhanced plaque VSMC apoptosis induced by agonistic anti-Fas antibody (apoptotic indices, 6.6+/-1.8% for control, 6.3+/-1.5% for DETA/NO, 26+/-1.8% for Fas, and 44+/-6.9% for Fas+DETA/NO). In isolated macrophages, NOS inhibitors reduced and NO donors increased surface Fas-L, indicating an NO-dependent autocrine enhancement of macrophage surface Fas-L.
Together, these data indicate that macrophage-derived NO is required for macrophage-induced VSMC apoptosis and that it acts by enhancing Fas-L/Fas interactions.
我们之前已经表明，巨噬细胞在体外通过细胞间接触和Fas-L/Fas相互作用诱导血管平滑肌细胞（VSMC）凋亡。由于一氧化氮（NO）是一种短程介质，我们测试了NO是否介导巨噬细胞诱导的VSMC凋亡。
一氧化氮合酶（NOS）抑制剂显著抑制巨噬细胞诱导的颈动脉斑块VSMC凋亡（凋亡指数，对照组为81±2.9%，N(G)-硝基-L-精氨酸甲酯[L-NAME]处理组为28.2±3.9%）以及冠状动脉中膜VSMC凋亡（凋亡指数，对照组为76±5.5%，L-NAME处理组为3.5±0.8%）。无活性对映体无作用（P>0.05）。培养的巨噬细胞而非VSMC表达诱导型NOS（而非神经元型NOS或内皮型NOS），同时伴有激活，并分泌每细胞1.51±0.3飞摩尔亚硝酸盐，这被L-NAME（100微摩尔/升）阻断。二乙三胺一氧化氮（DETA/NO）和硝普钠（NO供体）诱导VSMC细胞表面Fas表达，并增强激动性抗Fas抗体诱导的斑块VSMC凋亡（凋亡指数，对照组为6.6±1.8%，DETA/NO组为6.3±1.5%，Fas组为26±1.8%，Fas + DETA/NO组为44±6.9%）。在分离的巨噬细胞中，NOS抑制剂降低而NO供体增加表面Fas-L，表明巨噬细胞表面Fas-L的NO依赖性自分泌增强。
总之，这些数据表明巨噬细胞衍生的NO是巨噬细胞诱导VSMC凋亡所必需的，并且它通过增强Fas-L/Fas相互作用发挥作用。
