Meprin‐α (Mep1A) enhances TNF‐α secretion by mast cells and aggravates abdominal aortic aneurysms
- 17 March 2020
- journal article
- research article
- Published by Wiley in British Journal of Pharmacology
- Vol. 177 (12), 2872-2885
- https://doi.org/10.1111/bph.15019
Abstract
Background and Purpose Abdominal aortic aneurysm (AAA) rupture is mainly due to elastic lamina degradation. As a metalloendopeptidase, meprin‐α (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 and Key Results Mep1A mediated AAA formation by regulating the mast cell (MC) secretion of tumour necrosis factor alpha (TNF‐α), 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 (AngII)‐induced mouse AAA tissues using real‐time polymerase chain reaction (RT‐PCR), western blotting (WB) and immunohistochemistry. 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. Further mechanistic studies using RT‐PCR, WB, and enzyme‐linked immunosorbent assays demonstrated that Mep1A was expressed mainly in MCs, wherein it mediated TNF‐α expression. Mep1A inhibitor actinonin significantly inhibited TNF‐α secretion in MCs. TNF‐α 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‐α 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.Keywords
Funding Information
- National Natural Science Foundation of China (81370007, 81470579, 81622008, 91739107)
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