Abstract 727: Deletion of Acute Phase Reaction by hepatocyte-specific gp130-knock-out prevents neointima formation following carotid artery ligation.
Background: Disturbances in inflammatory factors, i.e. chemokines and cytokines are present in stable and unstable angina, hypertension and restenosis following angioplasty. Thereby, locally released chemokines and cytokines stimulate a hepatocyte-derived acute phase reaction which promotes the disease progression. The purpose of this study was to elucidate the role of the liver-derived acute phase proteins (APP) on neointima formation following left carotid artery (LCA) ligation in atherosclerosis-prone mice.
Methods and Results: Since APP are predominantly released from hepatocytes following interleukin 6 (IL-6) cytokine family stimulation via the receptor component gp130, we generated hepatocyte-gp130 knockout mice (alb-cretg) on an ApoE-deficient background (cre+;gp130flox/flox;apoE−/− = gp130−) and appropi-ate control (cre−;gp130flox/flox;apoE−/− = gp130flox) mice. Complete ligation of the LCA cranial to the carotid bifurcation was generated in 12 week old mice and biochemical, morphometric and immunohistological analysis were performed 3, 7 and 28 days later. The contra-lateral right carotid artery was used as control. In controls, serum amyloide A (SAA) as indicator-APP increased with a max. at 3 days, and returned to baseline after day 7. SAA-increase was completely abrogated in gp130− mice as determined by ELISA. Recruitment of leukocytes (CD45), monocytes (MOMA, CD36) infiltration was elevated at day 3 in controls and significantly reduced in gp130− mice. Subsequently, a -smooth muscle cell actin content at day 7 and 28 following LCA was significantly decreased in the media and the neointima of gp130− mice compared to controls. In addition, 28 days post LCA controls showed a significantly increase in neointima and media thickening which was completely blocked in gp130− mice (p<0.001). Subsequently, wild-type smooth muscle cells showed a significantly reduced proliferation pattern when stimulated with supernatants from IL-6-stimulated isolated gp130− hepatocytes.
Conclusions: gp130-dependent and hepatocyte-derived acute phase proteins promote vascular remodeling processes following vascular injury.