Background:
The development of thoracic aortic dissection (TAD) is closely related to the extracellular matrix (ECM) degradation and the vascular smooth muscle cell (VSMC) transformation from contractile to synthetic type. Legumain (Lgmn) degrades ECM components directly or by activating downstream signals. However, the role of Lgmn in the VSMC differentiation and the occurrence of TAD remains elusive.
Methods:
Microarray datasets concerning vascular dissection or aneurysm were downloaded from the Gene Expression Omnibus (GEO) database to screen differentially expressed genes (DEGs). Four-week-old male Lgmn knockout mice (Lgmn
-/-
), macrophage-specific Lgmn knockout mice (Lgmn
F/F
; LysM
Cre
) and RR-11a treated C57BL/6 mice were given β-aminopropionitrile monofumarate (BAPN, 1g/kg/day) in drinking water for four weeks for TAD modeling. RNA-Seq analysis was performed to recapitulate transcriptome profile changes. Cell interaction was examined in macrophage and VSMC coculture system. The reciprocity of macrophage derived Lgmn with integrin αvβ3 in VSMCs was tested by co-immunoprecipitation assay and colocalization analyses.
Results:
Microarray datasets from the GEO database indicated up-regulated Lgmn in aorta from TAD patients and Ang II induced aortic abdominal aneurysm (AAA) mice. Elevated Lgmn was evidenced in the aortas and serums from TAD patients and BAPN-induced TAD mice in this study. BAPN induced TAD progression was significantly ameliorated in Lgmn deficient or inhibited mice. Macrophage specific deletion of Lgmn alleviated BAPN induced ECM degradation. Unbiased profiler PCR-array and GO analysis displayed that Lgmn regulated VSMC phenotype transformation. Macrophage specific deletion of Lgmn ameliorated VSMC phenotypic switch in BAPN treated mice. Macrophage derived Lgmn inhibited VSMC differentiation in vitro as assessed by macrophages and VSMCs coculture system. Mechanically, macrophage derived Lgmn bound to integrin αvβ3 in VSMCs and blocked integrin αvβ3, therefore attenuating Rho GTPase activation, down-regulating VSMCs differentiation markers and eventually exacerbating TAD development. Rho-kinase (ROCK) inhibitor Y-27632 reversed the protective role of Lgmn depletion in vascular dissection.
Conclusions:
These findings indicate that Lgmn signaling may be a novel target for the prevention and treatment of TAD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.