吸烟诱导水解酶活性微囊泡在粥样斑块薄壁纤维帽进展中的研究
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摘要
目的：
吸烟明显增加动脉粥样硬化(Atherosclerosis, AS)斑块的破裂和破裂后血管内血栓形成的危险性,然而相关分子机制尚不明确。微囊泡(Micro vesciles, MVs)是细胞凋亡过程中产生的膜性囊状结构,近年研究证实动脉粥样斑块中存在大量单核巨噬细胞源性MVs,其致病力较母细胞更强、更持久,与AS斑块的进展密切相关。我们前期研究发现,TSE (Tobacco smoke extract, TSE)可增加单核细胞源性MVs的产生,该MVs携带组织因子,体外具有强大的促凝活性,解释了吸烟患者血液的高凝状态和斑块破裂后血栓形成的机制,但尚不能够解释吸烟患者AS斑块破裂的机制。因此,本研究旨在探讨TSE诱导巨噬细胞源性MVs是否具有蛋白水解酶活性,并探讨TSE诱导的蛋白水解酶活性MVs的分子性质和产生的分子信号通路机制。
方法：
1.PMA诱导人THP-1单核细胞建立巨噬细胞模型和贴壁筛选法分离诱导外周血单核巨噬细胞；
2.酶谱法和荧光底物分解法测量TSE诱导MVs水解酶活性；
3.在37℃应用Pro-MMP2与分离MVs体外共孵育1h,然后用酶谱法检测TSE诱导MVs激活Pro-MMP2的活性；
4.免疫荧双染色共聚焦显微镜观察TSE诱导巨噬细胞膜性基质金属蛋白酶1(membrane type1metalloproteinase, MT1-MMP)又称MMP14和细胞凋亡早期标志物磷脂酰丝氨酸(PS)表达及分布；
5. Western Blot检测TSE诱导巨噬细胞MMP14蛋白表达变化、MAPKs信号通路的激活和MVs携带MMP14情况；
6.应用流式细胞技术测量TSE诱导总MVs和MMP14+MVs数量；
7.应用凋亡抑制剂(caspase inhibitor, CASPi),观察TSE诱导MMP14+MVs的产生和活性；
8.应用MAPKs信号通路p38/ERK/JNK特异性抑制剂干预细胞后,观察TSE诱导MVs产生和活性。
结果：
1.成功应用PMA建立THP-1巨噬细胞和贴壁筛选法分离诱导人外周血原代单核巨噬细胞；
2.TSE诱导MVs可动态水解人工合成荧光底物肽段1和降解凝胶中天然底物明胶蛋白和胶原蛋白；
3.TSE诱导MVs可激活人工重组Pro-MMP2的活性,级联放大效应发挥水解胶原蛋白的活性；
4.TSE诱导巨噬细胞呈浓度和时间依赖性增加MMP14的表达,共聚焦显微镜显示MMP14在巨噬细胞膜上呈结节性表达增加且与细胞膜的早期凋亡标志分子PS共定位,提示TSE诱导MVs携带MMP14；
5.流式分析显示TSE可诱导巨噬细胞源性总MVs和MMP14+MVs的产生；
6. CASPi可明显抑制TSE诱导巨噬细胞源性总MWs和MMP14+MVs的产生,并抑制MVs水解酶活性,不影响巨噬细胞表达MMP14；
7.TSE可激活MAPKs信号通路,使通路重要蛋白p38、ERK和JNK磷酸化,其中p38和JNK磷酸化与TSE诱导的巨噬细胞表达MMP14有关,与ERK的磷酸化无关；
8.应用p38和JNK特异性抑制剂可明显减少TSE诱导的MMP14+MVs的数量和活性。
结论：
TSE干预巨噬细胞可明显增加蛋白水解酶活性MVs产生,与其携带的跨膜蛋白酶基质金属蛋白酶家族的MMP14有关,具有强大胶原和明胶蛋白酶的活性；TSE诱导的水解酶活性MVs产生与MAPKs信号通路中JNK和p38的磷酸化有关,与ERK磷酸化无关。我们的研究提示TSE诱导的蛋白水解酶活性MVs可能在AS斑块薄壁纤维帽形成中起着重要作用,是斑块破裂新的致病因子。
Objectives:
Cigarette smoking greatly increases the risk of atherosclerosis plaque rupture and subsequent intravascular thrombosis. However, the underlying mechanisms remain poorly understood. Increasing evidences have shown that the progression of atherosclerotic plaque was associated with accumulation of amounts of microvesicles (MVs) within the plaque lesion. Our group recently found that tobacco smoke extract (TSE) induces human monocytes/macrophages to generate tissue factor-positive MVs which have procoagulant activity. This finding may account for the increases content of tissue factor in atheromata from smokers and their increased risk of thrombotic occlusion after plaque rupture. But it would not necessarily explain the underlying mechanisms of plaque rupture. Therefore, in the present study, we sought to determine whether exposure of human macrophages to TSE induces the release MVs with proteolytic activity, what nature of the proteases on TSE-induced MVs might be, and what the molecular mechanisms might be responsible for their generation.
Methods:
1. The human THP-1cells were differentiated to macrophages using PMA. Primary human monocyte-derived macrophages (hMDMs) were prepared from fresh buffy coats by selecting monocytes by adherence followed by differentiation into macrophages.
2. The proteolytic activities of TSE-induced MVs were assayed by zymogram and flurometric analysis.
3. TSE-induced MVs were determined to activate pro-MMP2to gelatinase MMP2by zymogram after co-incubation with pro-MMP12for1hour at37℃.
4. Confocal microscopy was used to documents MMP14display and exteriorization of phosphatidylserine (PS) on the surface of TSE-treated macrophage.
5. Western Blot was used to detect the expression of MMP14and activation of MAPKs signaling pathways in the TSE-treated macrophages and MVs.
6. Flow cytometry were used to detect the generation of TSE-induced total-and MMP14-positive MVs.
7. Pretreatment macrophages with caspase inhibitor intervene the generation of TSE-induced total and proteolytic MVs.
8. Pretreatment macrophages with p38or JNK inhibitor intervene the generation of TSE-induced total-and proteolytic MVs.
Results
1. THP-1cell successfully differentiated to macrophages by PMA and got the hMDMs by adherence.
2. TSE-induced MVs significantly cleaved fluorogenic substrate I and degraded the native substrates gelatin and collagen in SDS gels.
3. Pre-coincubation of TSE-induced MVs with pro-MMP2can activate the MMP2gelatinase.
4. TSE exposure of macrophages significantly increased expression of MMP14in dose-and time-dependent manners. Confocal images showed a huge induction of cell surface MMP14and PS exteriorization on TSE-treated macrophages. The TSE-induced MVs were proved to carry MMP14by Western Blot.
5. Flow cytometry results showed that TSE exposure of macrophages significantly increased the generation of total-and MMP14-positive MVs.
6. Pretreatment of macrophage with CASPi significantly blocked the generation TSE-induced total-and MMP14-positive MVs and the proteolytic activity without affecting cellular expression of MMP14.
7. TSE exposure of macrophages increased the phosphoralytion of3major MAPKs including JNK, p38and ERK. The TSE-induced MMP14expression was associated with the phosphoralytion of JNK and p38, not ERK.
8. Pretreatment of macrophage with of JNK or p38inhibitor significantly blocked the generation of TSE-induced total-and MMP14-positive MVs, also blocked the proteolytic acitivity.
Conclusions:
TSE-induced macrophage-derived MVs carry substantial gelatinolytic and collagenolytic activities which can be attributed to a single, dominant, transmembrane protease of the MMP superfamily, namely MMP14. The production of these MVs relies on the activation of JNK and p38MAPKs, not ERK activation. The new pathogenic factors might play an important role in the formation of atherosclerosis thinning fibrous cap and plaque rupture.
吸烟明显增加动脉粥样硬化(Atherosclerosis, AS)斑块的破裂和破裂后血管内血栓形成的危险性,然而相关分子机制尚不明确。微囊泡(Micro vesciles, MVs)是细胞凋亡过程中产生的膜性囊状结构,近年研究证实动脉粥样斑块中存在大量单核巨噬细胞源性MVs,其致病力较母细胞更强、更持久,与AS斑块的进展密切相关。我们前期研究发现,TSE (Tobacco smoke extract, TSE)可增加单核细胞源性MVs的产生,该MVs携带组织因子,体外具有强大的促凝活性,解释了吸烟患者血液的高凝状态和斑块破裂后血栓形成的机制,但尚不能够解释吸烟患者AS斑块破裂的机制。因此,本研究旨在探讨TSE诱导巨噬细胞源性MVs是否具有蛋白水解酶活性,并探讨TSE诱导的蛋白水解酶活性MVs的分子性质和产生的分子信号通路机制。
方法：
1.PMA诱导人THP-1单核细胞建立巨噬细胞模型和贴壁筛选法分离诱导外周血单核巨噬细胞；
2.酶谱法和荧光底物分解法测量TSE诱导MVs水解酶活性；
3.在37℃应用Pro-MMP2与分离MVs体外共孵育1h,然后用酶谱法检测TSE诱导MVs激活Pro-MMP2的活性；
4.免疫荧双染色共聚焦显微镜观察TSE诱导巨噬细胞膜性基质金属蛋白酶1(membrane type1metalloproteinase, MT1-MMP)又称MMP14和细胞凋亡早期标志物磷脂酰丝氨酸(PS)表达及分布；
5. Western Blot检测TSE诱导巨噬细胞MMP14蛋白表达变化、MAPKs信号通路的激活和MVs携带MMP14情况；
6.应用流式细胞技术测量TSE诱导总MVs和MMP14+MVs数量；
7.应用凋亡抑制剂(caspase inhibitor, CASPi),观察TSE诱导MMP14+MVs的产生和活性；
8.应用MAPKs信号通路p38/ERK/JNK特异性抑制剂干预细胞后,观察TSE诱导MVs产生和活性。
结果：
1.成功应用PMA建立THP-1巨噬细胞和贴壁筛选法分离诱导人外周血原代单核巨噬细胞；
2.TSE诱导MVs可动态水解人工合成荧光底物肽段1和降解凝胶中天然底物明胶蛋白和胶原蛋白；
3.TSE诱导MVs可激活人工重组Pro-MMP2的活性,级联放大效应发挥水解胶原蛋白的活性；
4.TSE诱导巨噬细胞呈浓度和时间依赖性增加MMP14的表达,共聚焦显微镜显示MMP14在巨噬细胞膜上呈结节性表达增加且与细胞膜的早期凋亡标志分子PS共定位,提示TSE诱导MVs携带MMP14；
5.流式分析显示TSE可诱导巨噬细胞源性总MVs和MMP14+MVs的产生；
6. CASPi可明显抑制TSE诱导巨噬细胞源性总MWs和MMP14+MVs的产生,并抑制MVs水解酶活性,不影响巨噬细胞表达MMP14；
7.TSE可激活MAPKs信号通路,使通路重要蛋白p38、ERK和JNK磷酸化,其中p38和JNK磷酸化与TSE诱导的巨噬细胞表达MMP14有关,与ERK的磷酸化无关；
8.应用p38和JNK特异性抑制剂可明显减少TSE诱导的MMP14+MVs的数量和活性。
结论：
TSE干预巨噬细胞可明显增加蛋白水解酶活性MVs产生,与其携带的跨膜蛋白酶基质金属蛋白酶家族的MMP14有关,具有强大胶原和明胶蛋白酶的活性；TSE诱导的水解酶活性MVs产生与MAPKs信号通路中JNK和p38的磷酸化有关,与ERK磷酸化无关。我们的研究提示TSE诱导的蛋白水解酶活性MVs可能在AS斑块薄壁纤维帽形成中起着重要作用,是斑块破裂新的致病因子。
Objectives:
Cigarette smoking greatly increases the risk of atherosclerosis plaque rupture and subsequent intravascular thrombosis. However, the underlying mechanisms remain poorly understood. Increasing evidences have shown that the progression of atherosclerotic plaque was associated with accumulation of amounts of microvesicles (MVs) within the plaque lesion. Our group recently found that tobacco smoke extract (TSE) induces human monocytes/macrophages to generate tissue factor-positive MVs which have procoagulant activity. This finding may account for the increases content of tissue factor in atheromata from smokers and their increased risk of thrombotic occlusion after plaque rupture. But it would not necessarily explain the underlying mechanisms of plaque rupture. Therefore, in the present study, we sought to determine whether exposure of human macrophages to TSE induces the release MVs with proteolytic activity, what nature of the proteases on TSE-induced MVs might be, and what the molecular mechanisms might be responsible for their generation.
Methods:
1. The human THP-1cells were differentiated to macrophages using PMA. Primary human monocyte-derived macrophages (hMDMs) were prepared from fresh buffy coats by selecting monocytes by adherence followed by differentiation into macrophages.
2. The proteolytic activities of TSE-induced MVs were assayed by zymogram and flurometric analysis.
3. TSE-induced MVs were determined to activate pro-MMP2to gelatinase MMP2by zymogram after co-incubation with pro-MMP12for1hour at37℃.
4. Confocal microscopy was used to documents MMP14display and exteriorization of phosphatidylserine (PS) on the surface of TSE-treated macrophage.
5. Western Blot was used to detect the expression of MMP14and activation of MAPKs signaling pathways in the TSE-treated macrophages and MVs.
6. Flow cytometry were used to detect the generation of TSE-induced total-and MMP14-positive MVs.
7. Pretreatment macrophages with caspase inhibitor intervene the generation of TSE-induced total and proteolytic MVs.
8. Pretreatment macrophages with p38or JNK inhibitor intervene the generation of TSE-induced total-and proteolytic MVs.
Results
1. THP-1cell successfully differentiated to macrophages by PMA and got the hMDMs by adherence.
2. TSE-induced MVs significantly cleaved fluorogenic substrate I and degraded the native substrates gelatin and collagen in SDS gels.
3. Pre-coincubation of TSE-induced MVs with pro-MMP2can activate the MMP2gelatinase.
4. TSE exposure of macrophages significantly increased expression of MMP14in dose-and time-dependent manners. Confocal images showed a huge induction of cell surface MMP14and PS exteriorization on TSE-treated macrophages. The TSE-induced MVs were proved to carry MMP14by Western Blot.
5. Flow cytometry results showed that TSE exposure of macrophages significantly increased the generation of total-and MMP14-positive MVs.
6. Pretreatment of macrophage with CASPi significantly blocked the generation TSE-induced total-and MMP14-positive MVs and the proteolytic activity without affecting cellular expression of MMP14.
7. TSE exposure of macrophages increased the phosphoralytion of3major MAPKs including JNK, p38and ERK. The TSE-induced MMP14expression was associated with the phosphoralytion of JNK and p38, not ERK.
8. Pretreatment of macrophage with of JNK or p38inhibitor significantly blocked the generation of TSE-induced total-and MMP14-positive MVs, also blocked the proteolytic acitivity.
Conclusions:
TSE-induced macrophage-derived MVs carry substantial gelatinolytic and collagenolytic activities which can be attributed to a single, dominant, transmembrane protease of the MMP superfamily, namely MMP14. The production of these MVs relies on the activation of JNK and p38MAPKs, not ERK activation. The new pathogenic factors might play an important role in the formation of atherosclerosis thinning fibrous cap and plaque rupture.
引文
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