Human macrophage-induced vascular smooth muscle cell apoptosis requires NO enhancement of Fas/Fas-L interactions
Human macrophage-induced vascular smooth muscle cell apoptosis requires NO enhancement of Fas/Fas-L interactions
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DOI：
10.1161/01.atv.0000033517.48444.1a
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发表时间：
2002-10-01
影响因子：
8.7
通讯作者：
Bennett, MR
中科院分区：
文献类型：
--
作者：
Boyle, JJ;Weissberg, PL;Bennett, MR
目的：我们之前已经证明巨噬细胞通过细胞间接近和Fas- l /Fas相互作用诱导体外血管平滑肌细胞（VSMC）凋亡。由于NO是短程介质，我们测试了NO是否介导巨噬细胞诱导的VSMC凋亡。方法与结果- no合成酶（NOS）抑制剂显著抑制巨噬细胞诱导的颈动脉斑块VSMCs（凋亡指数，对照组81 +/- 2.9%，n - g -硝基- l -精氨酸甲酯[L-NAME]组28.2 +/- 3.9%）和冠状动脉内侧VSMCs（凋亡指数，对照组76 +/- 5.5%，L-NAME组3.5 +/- 0.8%）凋亡。无活性对映体无影响（P < 0.05）。培养的巨噬细胞，而非VSMCs，在活化的同时表达可诱导的NOS（但不包括神经元NOS或内皮NOS），每个细胞分泌1.51 +/- 0.3 fmol亚硝酸盐，L- name （100 mumol/L）阻断了亚硝酸盐的分泌。二乙烯三胺型一氧化氮（DETA/NO）和硝普钠（NO供体）诱导VSMC细胞表面Fas，并增强抗Fas激动性抗体诱导的斑块VSMC凋亡（凋亡指数：对照组6.6 +/- 1.8%，DETA/NO组6.3 +/- 1.5%，Fas组26 +/- 1.8%，Fas+DETA/NO组44 +/- 6.9%）。在离体巨噬细胞中，NOS抑制剂降低了表面Fas-L，而NO供体增加了表面Fas-L，表明巨噬细胞表面Fas-L的自分泌增强依赖于NO。综上所述，这些数据表明巨噬细胞来源的NO是巨噬细胞诱导的VSMC凋亡所必需的，并且它通过增强Fas- l /Fas相互作用起作用。
Objective-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.Methods and Results-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 mumol/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.Conclusions-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.