Mep1A enhances TNF‐alpha secretion by mast cells and aggravates abdominal aortic aneurysms

BACKGROUND AND PURPOSE: Abdominal aorticaneurysm (AAA) rupture is mainly due to elastic lamina degradation. As a metalloendopeptidase, meprin-alpha (Mep1A) critically modulates the activity of proteins and inflammatory cytokines in various diseases. Here, we sought to investigate the functional role of Mep1A in AAA formation and rupture. EXPERIMENTAL APPROACH: AAA tissues were detected by using real-time PCR (RT-PCR), western blotting (WB), and immunohistochemistry. Further mechanistic studies used RT-PCR, WB, and enzyme-linked immunosorbent assays. KEY RESULTS: Mep1A mediated AAA formation by regulating the mast cell (MC) secretion of TNF-alpha, which promoted matrix metalloproteinase (MMP) expression and apoptosis in smooth muscle cells (SMCs). Importantly, increased Mep1A expression was found in human AAA tissues and in angiotensin II-induced mouse AAA tissues. Mep1A deficiency reduced AAA formation and increased the survival rate of AAA mice. Pathological analysis showed that Mep1A deletion decreased elastic lamina degradation and SMC apoptosis in AAA tissues. Furthermore, Mep1A was expressed mainly in MCs, wherein it mediated TNF-alpha expression. Mep1A inhibitor actinonin significantly inhibited TNF-alpha secretion in MCs. TNF-alpha secreted by MCs enhanced MMP2 expression in SMCs and promoted SMC apoptosis. CONCLUSION AND IMPLICATIONS: Taken together, these data suggest that Mep1A may be vital in AAA pathophysiology by regulating TNF-alpha production by MCs. Knocking out Mep1A significantly decreased AAA diameter and improved AAA stability in mice. Therefore, Mep1A is a potential new therapeutic target in the development of AAA.