Administration of a Recombinant Secretory Leukocyte Protease Inhibitor Prevents Aortic Aneurysm Growth in Mice

Abstract

Aim Pharmacological interventions to inhibit the progression of aortic aneurysm (AA) have not yet been established. We previously reported that mesenchymal stem cells (MSCs) provide a potential foundation for less-invasive treatment of AA. Here, we investigated secretory proteins from MSC supernatants to clarify the therapeutic effects of MSCs. Furthermore, we treated AA mice with two anti-inflammatory proteins from among these secretory proteins to confirm their therapeutic effects. Methods and Results Protein profiles of MSC-secreted factors were analyzed using protein microarrays, and two anti-inflammatory proteins, namely progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI), were identified. Apolipoprotein E-deficient mice were continuously infused with angiotensin II via osmotic pump for 4 weeks to induce AA formation, and then recombinant rPGRN and/or rSLPI were administered intraperitoneally. Mice were sacrificed at 8 weeks, and aortas were analyzed for protein expression and also stained with Elastica van Gieson and with immunofluorescence to detect macrophages. Intraperitoneal administration of rSLPI inhibited AA growth more than rPGRN alone or combined rPGRN and rSLPI, by inducing the following effects: downregulation of inflammatory cytokines and chemokines, specifically IL-1β, IL-6, TNF-α, and MCP-1; reduced of NO production; decreased phosphorylated NF-κB levels; and less of elastin destruction and macrophage infiltration. Conclusions We identified anti-inflammatory proteins, including PGRN and SLPI, in MSC supernatants, and administration of rSLPI inhibited AA progression in mice. Protein-based therapies using SLPI could be an alternative, less-invasive treatment for AA.