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Syndecan-1 Inhibits Growth of Abdominal Aortic Aneurysm

Jiantao Xiao, Jing Wen, Carolyn A. Haller, Elliot L. Chaikof.
Emory University, Atlanta, Ga.

OBJECTIVES: Syndecan-1 is a member of a family of cell surface heparan sulfate proteoglycans that modulate inflammatory and growth-stimulating events relevant to acute tissue repair and chronic injury responses. We have previously demonstrated that macrophage-associated syndecan-1 is expressed during the course of abdominal aortic aneurysm (AAA) formation in human tissue and in a murine model of angiotensin II induced aneurysm formation. The present study investigated the role of syndecan-1 in a murine model of elastase-induced AAA.

METHODS: Adult male C57BL/6 wild-type (WT, n=43) and syndecan-1 knockout (KO, n=35) mice underwent transient elastase perfusion of the abdominal aorta to induce AAA. Aortic diameter (AD) was measured preperfusion, postperfusion, and at harvest on 1, 4, 7 and 14 days. AAA was defined as %ΔAD >100% between preperfusion and harvest. Aortas from each group and each time point were analyzed for inflammatory response by immunohistochemical staining and matrix metalloproteinase-2 (MMP-2) and MMP-9 activity by gelatin zymography. Macrophages were harvested 4 days after injection of 1 mL of 1% thioglycollate into the peritoneal cavity of WT or syndecan-1 KO mice. Conditioned media were collected, samples normalized by initial cell count and total protein assay, and proteolytic activity measured using elastin and collagen substrates.

RESULTS: All mice developed AAA at day 14, but syndecan-1 KO mice displayed a significantly greater extent of dilatation than WT mice (1.51±0.14 mm vs. 1.29±0.06 mm; p=0.00001; Figure 1). Histological analysis revealed robust expression of syndecan-1 at the site AAA formation in WT mice. Gelatin zymography demonstrated significantly greater levels of MMP-2 and MMP-9 activity in syndecan-1 KO mice at 7 days (proMMP-9: 0.816±0.125 vs. 0.602±0.090; p=0.0069; proMMP-2: 0.506±0.081 vs. 0.206±0.037; p=0.00001; Figure 2). A significantly higher level of proteolytic activity was observed in media obtained from KO macrophages than from wild type controls (p<0.05; Figure 3).

CONCLUSIONS: These results suggest that syndecan-1 acts as a negative regulator of proteolytic responses in the aortic wall during the course of AAA formation. Thus, modulating syndecan-1 expression could provide a useful strategy for limiting aneurysm growth. 
  
 

AUTHOR DISCLOSURES: J. Xiao, None; J. Wen, None; C.A. Haller, None; E.L. Chaikof, None.