Oxidative stress induces early-onset apoptosis of vascular smooth muscle cells and neointima formation in response to injury.
Oxidative stress induces early-onset apoptosis of vascular smooth muscle cells and neointima formation in response to injury.
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DOI：
10.1042/bsr20140122
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发表时间：
2015-06-12
影响因子：
4
通讯作者：
Vazquez-Padron RI
中科院分区：
文献类型：
--
作者：
Gomez C;Martinez L;Mesa A;Duque JC;Escobar LA;Pham SM;Vazquez-Padron RI
动脉损伤后VSMC凋亡的快速发生是由血管壁中活性氧的积累和氧化还原敏感的MAPK通路的激活驱动的。这一过程导致血管炎症和新生内膜增生。本研究剖析了损伤后血管重塑之前细胞凋亡快速发生的机制。使用大鼠球囊损伤模型，我们证明了一个显着数量的动脉血管平滑肌细胞（VSMC）进行凋亡后90分钟的程序。在接下来的3小时内，该凋亡波引起中膜细胞结构的显著损失（>90%），并伴随着血管壁中氧化应激副产物的显著积累。早期凋亡的VSMC富含p38丝裂原活化蛋白激酶（MAPK）和转录因子c-Jun，并分泌IL-6和GRO/KC到环境中，如使用多重珠测定。新生内膜厚度从第3天开始稳步增加，这是由于中膜明显再增殖的结果。在损伤后14天检测到的第二个凋亡波主要影响新生内膜，不足以控制增生。使用NAD（P）H氧化酶抑制剂VAS 2870或聚乙二醇化超氧化物歧化酶（PEG-SOD）抑制活性氧（ROS）的产生可显著降低第一次凋亡波期间的凋亡细胞数量，并显示损伤后30天新内膜-中膜厚度比降低的趋势。这些结果表明，氧化应激损伤诱导早发性凋亡的VSMC通过激活氧化还原敏感的MAPK促凋亡途径。这种重塑过程导致炎性细胞因子的局部积聚和中膜的再增殖，最终导致新生内膜形成。
The rapid onset of VSMC apoptosis after arterial injury is driven by the accumulation of reactive oxygen species in the vascular wall and the activation of redox-sensible MAPK pathways. This process leads to vascular inflammation and neointimal hyperplasia. The present study dissects the mechanisms underlying the rapid onset of apoptosis that precedes post injury vascular remodelling. Using the rat balloon injury model, we demonstrated that a significant number of arterial vascular smooth muscle cells (VSMC) undergo apoptosis at 90 min after the procedure. This apoptotic wave caused significant loss in media cellularity (>90%) over the next 3 h and was accompanied by a marked accumulation of oxidative stress by-products in the vascular wall. Early apoptotic VSMC were rich in p38 mitogen-activated protein kinase (MAPK) and the transcription factor c-Jun and secreted IL-6 and GRO/KC into the milieu as determined using multiplex bead assays. Neointima thickness increased steadily starting on day 3 as a result of pronounced repopulation of the media. A second apoptotic wave that was detected at 14 days after injury affected mostly the neointima and was insufficient to control hyperplasia. Suppression of reactive oxygen species (ROS) production using either the NAD(P)H oxidase inhibitor VAS2870 or pegylated superoxide dismutase (PEG-SOD) significantly decreased the number of apoptotic cells during the first apoptotic wave and showed a trend towards reduction in the neointima-to-media thickness ratio at 30 days post injury. These results indicate that oxidative stress in response to injury induces early-onset apoptosis of VSMC through the activation of redox-sensible MAPK pro-apoptotic pathways. This remodelling process leads to the local accumulation of inflammatory cytokines and repopulation of the media, which ultimately contribute to neointima formation.