Abstract 330: Macrophage Expressed Syndecan-1 in the Pathogenesis of Aortic Aneurysm
Introduction: Syndecan-1 is a cell surface heparan sulfate proteoglycan characterized by highly regulated expression during development, neoplasia, and wound repair. The ectodomain of syndecan-1 bears distinct heparan sulfate chains that are capable of binding a variety of ligands that modulate events relevant to acute tissue repair and chronic injury responses. The role of syndecan-1 in vascular inflammatory disease processes remains undefined. Previous studies in our lab have confirmed a dramatic upregulation of syndecan-1 co-localized in zones of macrophage infiltration in a murine model of abdominal aortic aneurysm (AAA). Using a syndecan-1 deficient mouse model, we assessed the hypothesis that macrophage expressed syndecan-1 is an important inflammatory modulator in the vascular wall.
Methods: Apolipoprotein E (ApoE) deficient and ApoE deficient/Syndecan-1 deficient mice were maintained on a proatherogenic diet and made hypertensive by infusion of angiotensin II (.75mg/kg/day). Mice were monitored for 2 weeks and sacrificed for AAA analysis and immunohistochemistry. Thioglycollate-elicited peritoneal macrophage were utilized to explore the functional role of syndecan-1 in macrophage. Protease activity was measured using gel zymography and fluorescent based microplate assays.
Results: ApoE/Syndecan-1 double knockout mice displayed a significantly higher rate in AAA formation (66%, n=30) verses the ApoE knockout control (33%, n=20), P<0.05. In addition, mortality was significantly increased in the ApoE/Syndecan-1 double knockout (33%) verses the ApoE control (5%), P<0.05. Most mice died from ascending aortic aneurysm rupture or ruptured AAA. Conditioned media from syndecan-1 deficient macrophage cultures displayed 3-fold higher elastase activity verses the wild-type control.
Conclusion: Loss of syndecan-1 results in increased mortality and increased incidence of AAA. Syndecan-1 may have a protective effect against unregulated inflammatory processes in the vascular wall.