Inhibition of endoplasmic reticulum stress signaling pathway: A new mechanism of statins to suppress the development of abdominal aortic aneurysm.
Inhibition of endoplasmic reticulum stress signaling pathway: A new mechanism of statins to suppress the development of abdominal aortic aneurysm.
复制标题
抑制内质网应激信号通路：他汀类药物抑制腹主动脉瘤发展的新机制。
DOI：
10.1371/journal.pone.0174821
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Yan J
中科院分区：
文献类型：
--
作者：
Li Y;Lu G;Sun D;Zuo H;Wang DW;Yan J
腹主动脉瘤（AAA）是一种潜在的致命疾病，一旦动脉瘤破裂生存率极低。他汀类药物可能对AAA的进展起有益作用，但其潜在机制尚不清楚。本研究旨在探讨他汀类药物是否通过抑制内质网（ER）应激信号通路抑制AAA的形成。用载脂蛋白e缺陷（ApoE−/−）小鼠，经血管紧张素II （Ang II）灌胃28天，建立具有临床意义的AAA模型。将小鼠随机分为4组：单纯生理盐水输注组；单独注射angii；angii输注加阿托伐他汀（20mg/kg/d）；angii输注加阿托伐他汀（30mg/kg/d）。另外，用腔外CaCl2诱导C57小鼠另造AAA模型，分为3组：假手术组、CaCl2诱导AAA组、CaCl2诱导AAA +阿托伐他汀（20mg/kg/d）组。然后分别切除主动脉组织作进一步检查。在体外研究中，将Ang II加或不加辛伐他汀治疗分别应用于血管平滑肌细胞（VSMCS）和Raw 264.7细胞。通过体内和体外实验评估内质网应激信号通路、细胞凋亡和炎症反应。我们发现高剂量的阿托伐他汀可以有效抑制angii或CaCl2诱导的AAA的发生和进展。在机制上，内质网应激和炎症反应的激活参与了Ang ii诱导的AAA形成。与单独治疗的小鼠相比，阿托伐他汀输注可显著降低Ang II诱导的ApoE−/−小鼠内质酸应激信号蛋白、凋亡细胞数量以及Caspase12和Bax的激活。此外，阿托伐他汀治疗后，IL-6、IL-8、IL-1β等促炎细胞因子均明显受到抑制。在体外实验中，辛伐他汀对血管平滑肌细胞和巨噬细胞内质网应激信号通路均有抑制作用，且其抑制作用呈剂量依赖性。此外，Angⅱ处理可诱导细胞凋亡。辛伐他汀对细胞凋亡的抑制作用在10 μmol/l时达到最大。我们认为，高剂量他汀类药物可以有效抑制AAA的发展，减少内质网应激、内质网应激相关的凋亡信号通路和炎症反应。这些发现揭示了他汀类药物抑制AAA形成/进展的新机制。
Abdominal aortic aneurysm (AAA) is a potentially lethal disease with extremely poor survival rates once the aneurysm ruptures. Statins may exert beneficial effects on the progression of AAA. However, the underlying mechanism is still not known. The purpose of the present study is to investigate whether statin could inhibit AAA formation by inhibiting the endoplasmic reticulum (ER) stress signal pathway. A clinically relevant AAA model was induced in Apolipoprotein E-deficient (ApoE−/−) mice, which were infused with angiotensin II (Ang II) for 28 days. These mice were randomly divided into following 4 groups: saline infusion alone; Ang II infusion alone; Ang II infusion plus Atorvastatin (20mg/kg/d); and Ang II infusion plus Atorvastatin (30mg/kg/d). Besides, another AAA model was induced in C57 mice with extraluminal CaCl2, which were divided into 3 groups: sham group, CaCl2-induced AAA group, and CaCl2-induced AAA plus atorvastatin (20mg/kg/d) group. Then, aortic tissue was excised for further examinations, respectively. In vitro studies, Ang II with or without simvastatin treatment were applied to the vascular smooth muscle cells (VSMCS) and Raw 264.7 cells. The ER stress signal pathway, apoptosis and inflammatory response were evaluated by in vivo and in vitro assays. We found that higher dose of atorvastatin can effectively suppress the development and progression of AAA induced by Ang II or CaCl2. Mechanistically, the activation of ER stress and inflammatory response were found involved in Ang II-induced AAA formation. The atorvastatin infusion significantly reduced ER stress signaling proteins, the number of apoptotic cells, and the activation of Caspase12 and Bax in the Ang II-induced ApoE−/− mice, compared with mice treated by Ang II alone. Furthermore, proinflammatory cytokines such as IL-6, IL-8, IL-1β were all remarkably inhibited after atorvastatin treatment. In vitro, the inhibitory effect of simvastatin on the ER stress signal pathway could be observed in both vascular smooth muscle cells and macrophages, and these inhibitory effects of statin were in a dose-dependent manner. In addition, apoptosis was induced with Ang II treatment. The maximal inhibitory effect of simvastatin on apoptosis was observed at 10 μmol/l. We conclude that higher dose of statin can effectively suppress the development of AAA, and reduce ER stress, ER stress-associated apoptosis signaling pathways, and inflammatory response. These findings reveal a new mechanism underlying the inhibitory effect of statin on AAA formation/progression.