Methamphetamine induces thoracic aortic aneurysm/dissection through C/EBPβ.
Methamphetamine induces thoracic aortic aneurysm/dissection through C/EBPβ.
复制标题
DOI：
10.1016/j.bbadis.2022.166447
复制
发表时间：
2022-09-01
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
胸主动脉瘤/夹层（TAAD）是一种临床表现多样、危及生命的疾病。虽然甲基苯丙胺（冰毒）和TAAD之间的联系经常被观察到，但冰毒滥用与主动脉瘤/夹层之间的因果关系尚未确定。本研究旨在确定甲基苯丙胺是否会导致主动脉瘤/夹层，并描述其潜在机制。采用赖氨酸氧化酶抑制剂β-氨基丙腈（BAPN）预处理SD大鼠，建立了新的TAAD模型。甲基苯丙胺与BAPN联用导致60%的大鼠胸主动脉瘤/夹层。BAPN+METH显著增加了基质金属蛋白酶（MMP） 2和MMP9的表达和活性，与弹性蛋白严重断裂和剥离一致。从机制上说，甲基安非他明通过增强母细胞对十足性瘫痪同源物3 （Smad3）和细胞外调节蛋白激酶（ERK1/2）信号传导，增加ccaat增强子结合蛋白β (C/EBPβ)的表达。甲基安非他明还能促进C/EBPβ与MMP2和MMP9启动子的结合。阻断C/EBPβ可显著减弱METH+ bapn诱导的TAAD和MMP2/MMP9的表达。此外，BAPN+METH通过C/ ebp β介导的IGFBP5/p53/PUMA信号通路促进主动脉内侧平滑肌细胞（SMC）凋亡。更重要的是，C/EBPβ、MMP2/MMP9和促凋亡蛋白的表达在人胸主动脉夹层患者的主动脉中增加，这表明动物研究中发现的机制可能与人类疾病有关。我们的研究表明，甲基苯丙胺暴露对TAAD有偶然的影响。C/EBPβ通过引起弹性蛋白断裂、中间细胞丢失和变性介导甲基化引入的TAAD形成。因此，C/EBPβ可能是TAAD临床诊断或治疗的潜在因素。
Thoracic aortic aneurysm/dissection (TAAD) is a life-threatening disease with diverse clinical manifestations. Although the association between methamphetamine (METH) and TAAD is frequently observed, the causal relationship between METH abuse and aortic aneurysm/dissection has not been established. This study was designed to determine if METH causes aortic aneurysm/dissection and delineate the underlying mechanism. A new TAAD model was developed by exposing METH to SD rats pre-treated with lysyl oxidase inhibitor β-aminopropionitrile (BAPN). Combination of METH and BAPN caused thoracic aortic aneurysm/dissection in 60% of rats. BAPN+METH significantly increased the expression and activities of both matrix metalloproteinase (MMP) 2 and MMP9, consistent with the severe elastin breakage and dissection. Mechanistically, METH increased CCAAT-enhancer binding protein β (C/EBPβ) expression by enhancing mothers against decapentaplegic homolog 3 (Smad3) and extracellular regulated protein kinase (ERK1/2) signaling. METH also promoted C/EBPβ binding to MMP2 and MMP9 promoters. Blocking C/EBPβ significantly attenuated METH+BAPN-induced TAAD and MMP2/MMP9 expression. Moreover, BAPN+METH promoted aortic medial smooth muscle cell (SMC) apoptosis through C/EBPβ-mediated IGFBP5/p53/PUMA signaling pathways. More importantly, the expression of C/EBPβ, MMP2/MMP9, and apoptosis-promoting proteins was increased in the aorta of human patients with thoracic aortic dissection, suggesting that the mechanisms identified in animal study could be relevant to human disease. Our study demonstrated that METH exposure has a casual effect on TAAD. C/EBPβ mediates METH-introduced TAAD formation by causing elastin breakage, medial cell loss and degeneration. Therefore, C/EBPβ may be a potential factor for TAAD clinical diagnosis or treatment.
登录
查看更多内容
DOI：
10.1126/science.1192149
发表时间：
2011-04-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Holm TM;Habashi JP;Doyle JJ;Bedja D;Chen Y;van Erp C;Lindsay ME;Kim D;Schoenhoff F;Cohn RD;Loeys BL;Thomas CJ;Patnaik S;Marugan JJ;Judge DP;Dietz HC
通讯作者：
Dietz HC
影响因子：
37.8
作者：
Bonderman, D;Gharehbaghi-Schnell, E;Lang, IM
通讯作者：
Lang, IM
来自平滑肌细胞的内质网应激依赖性微粒在胸主动脉瘤和夹层过程中促进内皮功能障碍
DOI：
10.1042/cs20170252
发表时间：
2017-06-01
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Jia LX;Zhang WM;Li TT;Liu Y;Piao CM;Ma YC;Lu Y;Wang Y;Liu TT;Qi YF;Du J
通讯作者：
Du J
Toll 样受体 4 通过星形胶质细胞中的 Caspase-11 信号通路介导甲基苯丙胺诱导的神经炎症。
影响因子：
4.8
作者：
Du SH;Qiao DF;Chen CX;Chen S;Liu C;Lin Z;Wang H;Xie WB
通讯作者：
Xie WB
影响因子：
20.1
作者：
Liu, Renjing;Lo, Lisa;Gamble, Jennifer R.
通讯作者：
Gamble, Jennifer R.