The Complement C3a-C3aR Axis Promotes Development of Thoracic Aortic Dissection via Regulation of MMP2 Expression
The Complement C3a-C3aR Axis Promotes Development of Thoracic Aortic Dissection via Regulation of MMP2 Expression
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补体 C3a-C3aR 轴通过调节 MMP2 表达促进胸主动脉夹层的发展
DOI：
10.4049/jimmunol.1601386
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发表时间：
2018-03-01
影响因子：
4.4
通讯作者：
Du, Jie
中科院分区：
文献类型：
--
作者：
Ren, Weihong;Liu, Yan;Du, Jie
胸主动脉夹层（TAD）一旦破裂，对患者来说是灾难性的，且目前尚无有效的药物治疗方法。补体激活所释放的过敏毒素与多种疾病相关。然而，补体系统在胸主动脉夹层中的作用尚不明确。我们发现，胸主动脉夹层患者血浆中C3a、C4a和C5a水平显著升高。在由单延胡索酸β - 氨基丙腈（BAPN）诱导的小鼠胸主动脉夹层发育过程中，也检测到循环C3a水平升高，且小鼠发生夹层的主动脉中C1q和备解素的表达增强。这些发现表明经典和替代补体途径均被激活。此外，在人和小鼠发生夹层的主动脉平滑肌细胞中，C3aR的表达明显增加，而敲除C3aR可显著抑制BAPN诱导的小鼠胸主动脉夹层的形成和破裂。在BAPN处理前后给予C3aR拮抗剂可减轻胸主动脉夹层的发展。我们发现，敲除C3aR可降低BAPN处理小鼠体内基质金属蛋白酶2（MMP2）的表达。另外，重组C3a刺激可增强受到机械牵张的平滑肌细胞中MMP2的表达和激活。最后，我们通过使用重组腺相关病毒在体内递送MMP2短发夹RNA，构建了MMP2基因敲低小鼠，并发现MMP2缺失可显著减少胸主动脉夹层的形成。因此，我们的研究表明，C3a - C3aR轴通过调节MMP2的表达促进胸主动脉夹层的发展。靶向C3a - C3aR轴可能是一种抑制胸主动脉夹层形成的策略。
Thoracic aortic dissection (TAD), once ruptured, is devastating to patients, and no effective pharmaceutical therapy is available. Anaphylatoxins released by complement activation are involved in a variety of diseases. However, the role of the complement system in TAD is unknown. We found that plasma levels of C3a, C4a, and C5a were significantly increased in patients with TAD. Elevated circulating C3a levels were also detected in the developmental process of mouse TAD, which was induced by b-aminopropionitrile monofumarate (BAPN) treatment, with enhanced expression of C1q and properdin in mouse dissected aortas. These findings indicated activation of classical and alternative complement pathways. Further, expression of C3aR was obviously increased in smooth muscle cells of human and mouse dissected aortas, and knockout of C3aR notably inhibited BAPNinduced formation and rupture of TAD in mice. C3aR antagonist administered pre-and post-BAPN treatment attenuated the development of TAD. We found that C3aR knockout decreased matrix metalloproteinase 2 (MMP2) expression in BAPN-treated mice. Additionally, recombinant C3a stimulation enhanced MMP2 expression and activation in smooth muscle cells that were subjected to mechanical stretch. Finally, we generated MMP2-knockdown mice by in vivo MMP2 short hairpin RNA delivery using recombinant adeno-associated virus and found that MMP2 deficiency significantly reduced the formation of TAD. Therefore, our study suggests that the C3a-C3aR axis contributes to the development of TAD via regulation of MMP2 expression. Targeting the C3a-C3aR axis may represent a strategy for inhibiting the formation of TAD.