Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovative Research Center for Cardiovascular Diseases, Beijing 100029, China.
Department of Pathology, Aviation General Hospital of China Medical University, Beijing 100012, China.
J Immunol. 2018 Mar 1;200(5):1829-1838. doi: 10.4049/jimmunol.1601386. Epub 2018 Jan 24.
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 β-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 BAPN-induced 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 C3aC3aR 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.
胸主动脉夹层（TAD）一旦破裂，对患者来说是毁灭性的，目前尚无有效的药物治疗方法。补体激活释放的过敏毒素参与多种疾病。然而，补体系统在 TAD 中的作用尚不清楚。我们发现 TAD 患者的血浆 C3a、C4a 和 C5a 水平显著升高。在β-氨基丙腈单富马酸盐（BAPN）诱导的小鼠 TAD 发育过程中，也检测到循环 C3a 水平升高，小鼠夹层主动脉中 C1q 和备解素表达增强。这些发现表明经典和替代补体途径被激活。此外，人源和鼠源夹层主动脉平滑肌细胞中 C3aR 的表达明显增加，C3aR 敲除显著抑制 BAPN 诱导的 TAD 形成和破裂。C3aR 拮抗剂在 BAPN 处理前后给药可减轻 TAD 的发展。我们发现 C3aR 敲除可降低 BAPN 处理小鼠的基质金属蛋白酶 2（MMP2）表达。此外，重组 C3a 刺激可增强机械拉伸作用下平滑肌细胞中 MMP2 的表达和激活。最后，我们通过体内重组腺相关病毒传递 MMP2 短发夹 RNA 生成 MMP2 敲低小鼠，并发现 MMP2 缺陷显著减少 TAD 的形成。因此，我们的研究表明，C3a-C3aR 轴通过调节 MMP2 表达促进 TAD 的发展。靶向 C3a-C3aR 轴可能是抑制 TAD 形成的一种策略。
