Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Collaborative Innovative Research Center for Cardiovascular Diseases, Beijing 100029, China.
Emergency and Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
Clin Sci (Lond). 2018 Mar 26;132(6):655-668. doi: 10.1042/CS20171529. Print 2018 Mar 30.
Thoracic aortic aneurysm and dissection (TAAD) is due to degeneration of the aorta and causes a high mortality rate, while molecular mechanisms for the development of TAAD are still not completely understood. In the present study, 3-aminopropionitrile (BAPN) treatment was used to induce TAAD mouse model. Through transcriptome analysis, we found the expression levels of genes associated with interleukin-3 (IL-3) signaling pathway were up-regulated during TAAD development in mouse, which were validated by real-time PCR. IL-3 positive cells were increased in TAAD mouse aortas, especially for smooth muscle cells (SMCs). IL-3 deficiency reduced BAPN-induced TAAD formation. We then examined the matrix metalloproteinases (MMPs) expression during TAAD formation in both wild-type and IL-3 deficient mice, showing that MMP12 were significantly down-regulated in IL-3 deficient aortas. Mechanistically, we found recombinant IL-3 could increase MMP12 production and activity from macrophages Silencing of IL-3 receptor β, which was mainly expressed in macrophages but not SMCs, diminished the activation of c-Jun N terminal kinase (JNK)/extracellular-regulated protein kinases 1/2 (ERK1/2)/AP-1 signals, and decreased MMP12 expression in IL-3 stimulated macrophages. Moreover, both circulating and aortic inflammation were decreased in IL-3 deficient aortas. Taken together, our results demonstrated that IL-3 stimulated the production of MMP12 from macrophages by a JNK- and ERK1/2-dependent AP-1 pathway, contributing to TAAD formation. Thus, the IL-3/IL-3Rβ/MMP12 signals activation may be an important pathological mechanism for progression of TAAD.
胸主动脉瘤和夹层（TAAD）是由于主动脉退化引起的，死亡率很高，而 TAAD 发展的分子机制仍不完全清楚。在本研究中，使用 3-氨基丙腈（BAPN）处理来诱导 TAAD 小鼠模型。通过转录组分析，我们发现与白细胞介素-3（IL-3）信号通路相关的基因表达水平在 TAAD 小鼠发展过程中上调，这通过实时 PCR 得到验证。TAAD 小鼠主动脉中的 IL-3 阳性细胞增加，特别是平滑肌细胞（SMCs）。IL-3 缺乏减少了 BAPN 诱导的 TAAD 形成。然后，我们检查了野生型和 IL-3 缺乏型小鼠中 TAAD 形成过程中的基质金属蛋白酶（MMPs）表达，结果表明 MMP12 在 IL-3 缺乏型主动脉中显著下调。从机制上讲，我们发现重组 IL-3 可以增加巨噬细胞中的 MMP12 产生和活性。IL-3 受体β（主要在巨噬细胞中表达，而不在 SMC 中）沉默，减弱了 c-Jun N 端激酶（JNK）/细胞外调节蛋白激酶 1/2（ERK1/2）/AP-1 信号的激活，并减少了 IL-3 刺激的巨噬细胞中 MMP12 的表达。此外，IL-3 缺乏型主动脉中的循环和主动脉炎症均减少。总之，我们的结果表明，IL-3 通过 JNK 和 ERK1/2 依赖的 AP-1 途径刺激巨噬细胞产生 MMP12，促进 TAAD 形成。因此，IL-3/IL-3Rβ/MMP12 信号的激活可能是 TAAD 进展的重要病理机制。
