Abstract 1706: Neointima Formation Following Carotid Artery Ligation is Inhibited in Mice Lacking the Gp130-Dependent Acute Phase Response
Introduction: Vascular remodeling in atherosclerosis and restenosis following angioplasty involve vascular smooth muscle cell (VSMC) migration/proliferation and local inflammation as well as circulating inflammatory mediators such as acute phase proteins. Here we investigated the influence of the systemic acute phase response on neointima formation following carotid artery ligation in atherosclerosis-prone mice.
Methods and results: Elimination of the systemic acute phase reaction was achieved by hepatocyte-specific knockout of the gp130 gene in apoE−/− mice (=gp130−) and compared to respective control mice (=gp130flox). Neointima formation was induced by complete permanent ligation of the left common carotid artery (LCA) near to the carotid bifurcation. LCA ligation led to an early activation of the systemic acute phase reaction in gp130flox mice on day 3 as measured by plasma serum amyloid A (SAA) levels which was completely blocked in gp130− mice (ELISA, P < 0.01, n = 6). 28 days post LCA ligation gp130flox mice exhibited a strong neointima formation as determined by quantitative morphometry which was suppressed in gp130− mice by ~75% (P < 0.01, n = 6). Immunohis-tochemical analysis of carotids from gp130− mice after LCA ligation revealed a reduction of VSMC cell content by 70% (P < 0.01, n = 6) and subsequently a reduction of VSMC proliferation by 78% (P < 0.01, n = 6) compared to gp130flox mice as assessed by α-SMC-actin and Ki67 staining, respectively. To elucidate the potential underlying mechanism, conditioned medium of interleukin-6 (IL-6) stimulated hepatocytes from gp130flox and gp130− mice was collected. IL-6 induced release of SAA was completely abrogated in hepatocytes isolated from gp130− mice. VSMC stimulated with conditioned medium from gp130− mice showed significantly reduced migration and proliferation (P < 0.05, n = 4) compared to conditioned medium from gp130flox mice as assessed by transwell inserts, scratch assay and BrdU-incorporation whereas recombinant SAA dose-dependently induced both, migration and proliferation of VSMC (P < 0.05, n = 4).
Conclusion: In summary, our data identify an important role for the gp130-dependent acute phase reaction in vascular remodeling.