Abstract 5776: Deletion of the Systemic Gp130-dependent Acute Phase Response Inhibits Neointima Formation Following Carotid Artery Ligation
Background: Inflammation and vascular remodeling are hallmarks of atherosclerosis, hypertension and restenosis following angioplasty. Recently we demonstrated a crucial role of the hepatocyte gp130-dependent systemic acute phase response for atherogenesis (JEM 2007). Now we have elucidated the role of the hepatocyte gp130-dependent systemic acute phase response for vascular remodeling following experimental carotid artery ligation.
Methods and Results: Mice with a hepatocyte-specific gp130-k.o. on an apoE−/− background (gp130−) were compared to control mice (gp130flox). Vascular remodeling was induced by permanent ligation of the left common carotid artery. This activated the systemic acute phase reaction in gp130flox mice as measured by acute phase serum amyloid A (SAA1) plasma levels and vascular SAA1 content and was completely abrogated in gp130− mice (ELISA, SAA1 immunostaining, P<0.05, n=5). Morphometric analysis of the carotid artery revealed severe neointima formation and media thickening 28 days post ligation in gp130flox mice which was inhibited in gp130− mice (P<0.01, n=6). Carotid segments from gp130− showed less smooth muscle cells (SMCs), proliferation and monocyte recruitment (α-SMC actin, Ki-67, MOMA-2 immunostaining, P<0.01, n=6). To evaluate the impact of the gp130-dependent systemic acute phase response on SMCs, hepatocytes from gp130flox and gp130− mice were stimulated with the gp130-activating interleukin (IL)-6. IL-6-induced secretion of SAA1 was completely abolished in gp130− hepatocytes (ELISA, P<0.01, n=4). Moreover, when stimulated with supernatants from gp130− hepatocytes, SMCs showed significantly less migration and proliferation compared to supernatants from gp130flox hepatocytes (transwell, scratch assay, BrdU-incorporation, P<0.01, n=4). Finally, recombinant SAA1 induced SMC migration and proliferation (transwell, scratch assay, BrdU-incorporation, P<0.01, n=3– 4) and SAA1-injection following carotid artery ligation restored vascular remodeling in gp130− mice (P<0.01, n=3–5).
Conclusion: These results imply a critical role of the gp130-dependent systemic acute phase response for vascular inflammation, SMC migration and proliferation and subsequently for vascular remodeling.