The Complement C3a–C3aR Axis Promotes Development of Thoracic Aortic Dissection via Regulation of MMP2 Expression

Abstract

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.

CD40L promotes development of acute aortic dissection via induction of inflammation and impairment of endothelial cell function

“…Thus, we tested many pro-inflammatory chemokines and endothelial adhesion molecules which have been validated to be markers of endothelial cells CD40L-CD40 interaction in order to identify endothelial cells dysfunction. Of them, VCAM-1, E-selectin, P-selectin, MCP-1, IL-6, MMP-2 and MMP-9 were previously demonstrated to promote AAD formation [ 3 , 5 , 28 – 31 ]. DU XM et al observed TNF-α mRNA was elevated in blood samples of AAD patients [ 32 ].…”

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

“…In addition to its role in ischemic stroke, C3aR was also reported to be implicated in the progression of thoracic aortic dissection and myocardial infarction, which are also vascular diseases [175, 176]. In a model of brain inflammation induced by LPS injection, the results showed that C3aR played a critical role in endothelial activation and leukocyte recruitment when LPS was injected into the brain [177].…”

Selective and marked decrease of complement receptor C5aR2 in human thoracic aortic aneurysms: a dysregulation with potential inflammatory effects

“…There are a few other studies on complement receptors in thoracic aortic dilatation and dissection. Ren et al has reported systemic complement activation and upregulation of C3aR in human TAA suggesting that the C3a-C3aR1 axis promotes TAA rupture 25. However, their control groups consisted of plasma from healthy volunteers and aortic tissue from patients undergoing heart transplantation without any additional information on the presence of atherosclerosis.…”