Apoptosis Signal-Regulating Kinase 1 Deficiency Attenuates Vascular Injury-Induced Neointimal Hyperplasia by Suppressing Apoptosis in Smooth Muscle Cells
Apoptosis Signal-Regulating Kinase 1 Deficiency Attenuates Vascular Injury-Induced Neointimal Hyperplasia by Suppressing Apoptosis in Smooth Muscle Cells
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DOI：
10.1016/j.ajpath.2012.10.008
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发表时间：
2013-02-01
影响因子：
6
通讯作者：
Sasaguri, Yasuyuki
中科院分区：
文献类型：
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作者：
Tasaki, Takashi;Yamada, Sohsuke;Sasaguri, Yasuyuki
凋亡信号调节激酶1（apoptosis signal regulating kinase 1，ASK 1）是一种在应激诱导的细胞凋亡中起重要作用的丝裂原活化蛋白激酶激酶。最近，我们报道了在高脂血症诱导的动脉粥样硬化模型中，ASK 1和载脂蛋白E双敲除小鼠中抑制的巨噬细胞凋亡加速了动脉粥样硬化斑块。然而，平滑肌细胞（SMC）凋亡在动脉粥样硬化发病中的作用仍不清楚。我们研究了ASK 1缺陷小鼠（ASK 1（-/-））结扎颈动脉3周后的新生内膜重塑。与野生型小鼠相比，ASK 1（-/-）小鼠的内膜形成明显受到更多的抑制，相反地表现为ASK 1缺陷的潜在抗动脉粥样硬化方面，其特征在于SMC较少和胶原合成较少;凋亡SMC、浸润T淋巴细胞和微血管较少，与管腔内皮细胞凋亡减少相关。ASK 1（-/-）小鼠的损伤动脉也显示促凋亡标记物、粘附分子和促炎信号因子的表达显著下调。此外，肿瘤坏死因子-α诱导的凋亡在培养的ASK 1（-/-）小鼠主动脉平滑肌细胞中被显著抑制。这些发现表明，ASK 1通过增加新血管形成和/或增强SMC和内皮细胞凋亡加速机械损伤诱导的血管重塑和激活SMC迁移。ASK 1的表达，尤其是在SMC中，可能是至关重要的，并且可能负责各种促动脉粥样硬化功能，并且SMC凋亡似乎在该模型中是有害的。(Am J Pathol 2013，182：597-609; http：//dx·doi·org/10·1016/j·ajpath·2012·10·008）
Apoptosis signal regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a crucial role in stress-induced apoptosis. Recently, we have reported that suppressed macrophage apoptosis in ASK1 and apolipoprotein E double-knockout mice accelerates atheromatous plaques in the hyperlipidemia-induced atherosclerotic model. However, the pathogenic role of smooth muscle cell (SMC) apoptosis in atherosclerosis still remains unclear. We investigated neointimal remodeling in ligated carotid arteries of ASK1-deficient mice (ASK1(-/-)) for 3 weeks. ASK1(-/-) mice had significantly more suppressed intimal formation, inversely manifesting as potential anti-atherogenic aspects of ASK1 deficiency, characterized by fewer SMCs and Less collagen synthesis; and fewer apoptotic SMCs, infiltrating T lymphocytes, and microvessels, associated with decreased apoptosis of Luminal endothelial cells, compared with those of wild-type mice. Injured arteries of ASK1(-/-) mice also showed significantly down-regulated expression of pro-apoptotic markers, adhesion molecules, and pro-inflammatory signaling factors. Moreover, tumor necrosis factor-alpha-induced apoptosis was markedly suppressed in cultured aortic SMCs from ASK1(-/-) mice. These findings suggest that ASK1 accelerates mechanical injury-induced vascular remodeling with activated SMC migration via increased neovascularization and/or enhanced SMC and endothelial cell apoptosis. ASK1 expression, especially in the SMCs, might be crucial, and reciprocally responsible for various pro-atherogenic functions, and SMC apoptosis seems to be detrimental in this model. (Am J Pathol 2013, 182: 597-609; http://dx.doi.org/10.1016/j.ajpath.2012.10.008)