Cigarette smoke extract induces ferroptosis in vascular smooth muscle cells
Cigarette smoke extract induces ferroptosis in vascular smooth muscle cells
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DOI：
10.1152/ajpheart.00559.2019
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发表时间：
2020-03-01
影响因子：
4.8
通讯作者：
Takahashi, Masafumi
中科院分区：
文献类型：
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作者：
Sampilvanjil, Ariunaa;Karasawa, Tadayoshi;Takahashi, Masafumi
吸烟是主动脉瘤和夹层的主要危险因素;然而，吸烟和这些主动脉疾病之间没有因果关系已被证明。在本研究中，我们研究了香烟烟雾影响血管壁细胞的机制，发现香烟烟雾提取物（CSE）诱导一种新形式的调节性细胞死亡，称为血管平滑肌细胞（VSMCs）中的铁凋亡。CSE显著诱导A7 r5细胞和原代大鼠VSMCs的细胞死亡。但在内皮细胞中不存在，其可被特异性铁凋亡抑制剂[ferrostatin-1（Fer-1）和livestatin-1]和铁螯合剂（去铁胺）完全抑制。GSH前体（N-乙酰半胱氨酸）和NADPH氧化酶抑制剂[氯化二苯碘铵（DPI）]可部分抑制CSE诱导的VSMC死亡，但不能被泛半胱天冬酶抑制剂（Z-VAD）抑制。caspase-1（Z-YVAD）或坏死性凋亡（necrostatin-1）。CSE还上调A7 r5细胞中的IL-1 β、IL-6、TNF-α、基质金属蛋白酶（MMP）-2、MMP-9和TIMP-1（金属蛋白酶的组织抑制剂），其被Fer-1抑制。此外，CSE诱导Ptgs 2 mRNA的上调，脂质过氧化和细胞内GSH耗竭。这是铁下垂的主要特征。CSE的主要成分丙烯醛和甲基乙烯基酮可诱导VSMC铁凋亡。此外，CSE引起离体血管中膜VSMC丢失。电子显微镜分析显示CSE处理的动脉瘤中膜VSMCs的线粒体损伤和断裂。所有这些表现都被Fer-1部分恢复。这些发现表明，铁凋亡是CSE诱导的VSMC死亡的原因，并提示铁凋亡是预防主动脉瘤和夹层的潜在治疗靶点。新&值得注意的是，香烟烟雾提取物（CSE）诱导的大鼠血管平滑肌细胞（VSMCs）细胞死亡可被特异性铁凋亡抑制剂和铁螯合剂完全抑制。CSE还诱导Ptgs 2 mRNA的上调、脂质过氧化和细胞内GSH耗竭，这些是铁凋亡的关键特征。CSE引起离体血管中膜VSMC丢失。这些发现表明，铁凋亡是CSE诱导的VSMC死亡的原因。
Cigarette smoking is a major risk factor for aortic aneurysm and dissection; however, no causative link between smoking and these aortic disorders has been proven. In the present study, we investigated the mechanism by which cigarette smoke affects vascular wall cells and found that cigarette smoke extract (CSE) induced a novel form of regulated cell death termed ferroptosis in vascular smooth muscle cells (VSMCs). CSE markedly induced cell death in A7r5 cells and primary rat VSMCs. but not in endothelial cells, which was completely inhibited by specific ferroptosis inhibitors [ferrostatin-1 (Fer-1) and Liproxstatin-1] and an iron chelator (deferoxamine). CSE-induced VSMC death was partially inhibited by a GSH precursor (N-acetyl cysteine) and an NADPH oxidase inhibitor [diphenyleneiodonium chloride (DPI)], but not by inhibitors of pan-caspases (Z-VAD). caspase-1 (Z-YVAD), or necroptosis (necrostatin-1). CSE also upregulated IL-1 beta, IL-6, TNF-alpha, matrix metalloproteinase (MMP)-2, MMP-9, and TIMP-1 (tissue inhibitor of metalloproteinase)in A7r5 cells, which was inhibited by Fer-1. Furthermore, CSE induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion. which are key features of ferroptosis. VSMC ferroptosis was induced by acrolein and methyl vinyl ketone, major constituents of CSE. Furthermore, CSE caused medial VSMC loss in ex vivo aortas. Electron microscopy analysis showed mitochondrial damage and fragmentation in medial VSMCs of CSE-treated aortas. All of these manifestations were partially restored by Fer-1. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death and suggest that ferroptosis is a potential therapeutic target for preventing aortic aneurysm and dissection.NEW & NOTEWORTHY Cigarette smoke extract (CSE)-induced cell death in rat vascular smooth muscle cells (VSMCs) was completely inhibited by specific ferroptosis inhibitors and an iron chelator. CSE also induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. CSE caused medial VSMC loss in ex vivo aortas. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death.