Involvement of macrophage-derived exosomes in abdominal aortic aneurysms development
Involvement of macrophage-derived exosomes in abdominal aortic aneurysms development
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巨噬细胞来源的外泌体参与腹主动脉瘤的发展
DOI：
10.1016/j.atherosclerosis.2019.08.016
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发表时间：
2019-10-01
期刊：
影响因子：
5.3
通讯作者：
Xiang, Meixiang
中科院分区：
文献类型：
--
作者：
Wang, Yidong;Jia, Liangliang;Xiang, Meixiang
背景和目标：腹主动脉瘤（AAA）以炎性细胞浸润、细胞外基质（ECM）降解和血管平滑肌细胞（VSMCs）功能障碍为特征。最近的研究报道，外泌体介导细胞间通讯，并参与不同的疾病。外泌体是否在AAA中发挥作用尚不清楚。因此，本研究评估了外泌体在AAA development.Methods的功能：外泌体在人类和磷酸钙（CaPO 4）诱导的AAA组织中的存在通过免疫荧光染色的CD 63和阿利克斯。将GW 4869（一种外泌体生物发生的抑制剂）腹腔内注射到CaPO 4诱导的AAA组织中，以评估外泌体抑制对AAA发展的影响。为了探索潜在的机制，将人单核细胞系THP-1分化为巨噬细胞，并从巨噬细胞收集外泌体。用巨噬细胞来源的exosomes处理VSMCs，并检测基质金属蛋白酶-2（MMP-2）的表达。结果：在人和小鼠的血管外膜中均检测到了外泌体的存在。它们主要在巨噬细胞簇中表达。腹腔注射GW 4869两周可显著减弱CaPO 4诱导的AAA的进展，保持弹性蛋白的完整性并降低MMP-2的表达。类似地，GW 4869的施用抑制了全身性和淋巴细胞外泌体的产生。在体外，用巨噬细胞来源的外泌体处理提高了人VSMC中MMP-2的表达，而用GW 4869预处理则消除了这些作用。还发现，JNK和p38通路介导的MMP-2的生产在VSMCs治疗后与巨噬细胞来源的exosomes.Conclusions：这项研究表明，来自巨噬细胞的exosomes参与AAA的发病机制。巨噬细胞来源的外泌体通过JNK和p38途径触发VSMC中MMP-2的表达GW 4869补充减弱小鼠中CaPO 4诱导的AAA。
Background and aims: Abdominal aortic aneurysm (AAA) is characterized by infiltration of inflammatory cells, extracellular matrix (ECM) degradation, and dysfunction of vascular smooth muscle cells (VSMCs). Recent studies reported that exosomes mediate intercellular communication and are involved in different diseases. Whether exosomes play a role in AAA is poorly understood. Hence, this study evaluated the function of exosomes in AAA development.Methods: The presence of exosomes in human and calcium phosphate (CaPO4)-induced AAA tissues was determined by immunofluorescence staining of CD63 and Alix. GW4869, an inhibitor of exosome biogenesis, was intraperitoneally injected into CaPO4-induced AAA tissues to evaluate the effects of exosomal inhibition on AAA development. To explore the underlying mechanisms, the human monocytic cell line THP-1 was differentiated into macrophages, and exosomes were collected from macrophages. VSMCs were treated with macrophagederived exosomes, and the expression of matrix metalloproteinase-2 (MMP-2) was evaluated. The activation of mitogen-activated protein kinases (MAPKs) pathways was also investigated in vitro and in vivo.Results: Exosomes were detected in the adventitia of aneurysmal tissues obtained from humans and mice. They were mainly expressed in clusters of macrophages. Intraperitoneal injection of GW4869 for two weeks significantly attenuated the progression of CaPO4-induced AAA, preserved elastin integrity and decreased MMP-2 expression. Similarly, administration of GW4869 suppressed the systemic and aneurysmal exosome generation. In vitro, treatment with macrophage-derived exosomes elevated MMP-2 expression in human VSMCs, while pretreatment with GW4869 abolished these effects. It was also found that JNK and p38 pathways mediated the production of MMP-2 in VSMCs following treatment with macrophage-derived exosomes.Conclusions: This study suggests that exosomes derived from macrophages are involved in the pathogenesis of AAA. Macrophage-derived exosomes trigger MMP-2 expression in VSMC via JNK and p38 pathways. GW4869 supplementation attenuates CaPO4-induced AAA in mice.