Abstract 1197: Blockade Of IFN-γ Inducible Protein 10 Improves Reendothelialization And Attenuates Neointimal Formation After Vascular Injury
Background: Human studies suggest that IFN-γ and the IFN-γ inducible protein 10 (IP10)/chemokine receptor 3 (CXCR3) axis plays a fundamental role in the pathophysiology of coronary restenosis in patients. CXCR3 is expressed on T cells and monocytes and regulates, as a proinflammatory response induced by IFN-γ, chemotaxis of inflammatory cells to the site of vascular injury. In addition, IP10 has been shown to reduce endothelial motility and tube formation capability.
Methods: We wanted to analyze the role of CXCR3/IP10 in neointima formation utilizing a mouse model of wire injury of the femoral artery in CXCR3 knockout (CXCR3−/−) mice and in mice treated with polyclonal antibodies against the CXCR3 ligands IP10 and monokine induced by IFN-γ (MIG).
Results: Using realtime RT-PCR we found a profound upregulation of IP10 mRNA in femoral arteries of wildtype mice 7 days after injury compared to vessels of uninjured controls. At the same time, systemic IP10 serum concentrations were significantly increased in injured mice. Morphometry revealed that CXCR3−/− mice developed significantly less neointima 14 days after wire injury compared to wildtype mice resulting in a significantly reduced lumen loss. Moreover, treatment with polyclonal antibody cocktail against IP10 and MIG led to similar reduction of neointima formation after wire-injury. As expected we found a reduced inflammatory response in CXCR3−/− and antibody-treated mice after wire injury measured by a decreased recruitment of CD3+ T cells and CD45+ leukocytes. Immunohistochemistry revealed that both CXCR3−/− and antibody-treated mice showed an increased reendothelialization, measured by the development of a monolayer of CD31+ endothelial cells compared to their respective controls. Finally we found a significant negative correlation between the extent of neointima formation and the actual endothelial status (R2=0.2928, p<0.01).
Conclusion: The CXCR3/IP10 axis plays a pivotal role of the in the inflammatory response after vascular injury. Moreover, blockade of CXCR3 or IP10/MIG results in improved reendothelialization and reduced neointima formation. Our data support the notion, that interfering with the CXCR3/IP10 system may represent a novel therapeutic target to reduce restenosis.