Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou 510515, PR China; Zhangzhou Health Vocational College, Zhangzhou 363000, PR China.
Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou 510515, PR China.
Biochim Biophys Acta Mol Basis Dis. 2022 Sep 1;1868(9):166447. doi: 10.1016/j.bbadis.2022.166447. Epub 2022 May 25.
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 MMP2 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.
胸主动脉瘤/夹层（TAAD）是一种具有多种临床表现的危及生命的疾病。尽管经常观察到冰毒（METH）与 TAAD 之间的关联，但 METH 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 METH 是否会导致主动脉瘤/夹层，并阐明潜在机制。
通过将赖氨酸氧化酶抑制剂β-氨基丙腈（BAPN）预处理的 SD 大鼠暴露于 METH，开发了一种新的 TAAD 模型。METH 和 BAPN 的联合作用导致 60%的大鼠发生胸主动脉瘤/夹层。BAPN+METH 显著增加了基质金属蛋白酶 MMP2 和 MMP9 的表达和活性，与严重的弹性蛋白断裂和夹层一致。在机制上，METH 通过增强母亲抗 decapentaplegic 同源物 3（Smad3）和细胞外调节蛋白激酶（ERK1/2）信号传导来增加 CCAAT 增强子结合蛋白β（C/EBPβ）的表达。METH 还促进了 C/EBPβ 与 MMP2 和 MMP9 启动子的结合。阻断 C/EBPβ 可显著减轻 METH+BAPN 诱导的 TAAD 和 MMP2/MMP9 表达。此外，BAPN+METH 通过 C/EBPβ 介导的 IGFBP5/p53/PUMA 信号通路促进主动脉中层平滑肌细胞（SMC）凋亡。更重要的是，在胸主动脉夹层患者的主动脉中，C/EBPβ、MMP2/MMP9 和促进凋亡蛋白的表达增加，这表明在动物研究中确定的机制可能与人类疾病相关。
我们的研究表明，METH 暴露对 TAAD 有因果关系。C/EBPβ 通过引起弹性蛋白断裂、中膜细胞丢失和变性来介导 METH 引起的 TAAD 形成。因此，C/EBPβ 可能是 TAAD 临床诊断或治疗的潜在因素。
