title: Hepatocyte gp130 deficiency reduces vascular remodeling after carotid artery ligation.
abstract: Inflammation and vascular remodeling are hallmarks of atherosclerosis, hypertension, and restenosis after angioplasty. Here we investigated the role of the hepatocyte gp130-dependent systemic acute phase response on vascular remodeling after carotid artery ligation. Mice with a hepatocyte-specific gp130 knockout on an apolipoprotein E(-/-) background (gp130-) were compared with control mice (gp130(flox)). Vascular remodeling was induced by permanent ligation of the left common carotid artery. This, in turn, activated the systemic acute phase reaction in gp130(flox) mice, as measured by serum amyloid A plasma levels, which was completely abrogated in gp130- mice (P<0.05). Morphometric analysis of the carotid artery revealed severe neointima formation and media thickening 28 days after ligation in gp130(flox) mice, which was suppressed in gp130- mice (P<0.01). Serial sections from gp130- carotid segments showed significantly less smooth muscle cell (SMC) proliferation and monocyte recruitment (P<0.01). To evaluate the impact of the gp130-dependent systemic acute phase response on SMCs, hepatocytes from gp130(flox) and gp130- mice were stimulated with interleukin 6. Interleukin 6-induced secretion of serum amyloid A was completely abolished in gp130- hepatocytes (P<0.01). Moreover, when stimulated with supernatants from gp130- hepatocytes, SMCs showed significantly less migration and proliferation compared with supernatants from gp130(flox) hepatocytes (P<0.01). Recombinant serum amyloid A induced SMC migration and proliferation (P<0.05) and serum amyloid A injection after carotid artery ligation restored vascular remodeling in gp130- mice (P<0.01). These results imply a critical role for the gp130-dependent systemic acute phase response for vascular inflammation and SMC migration, as well as proliferation, and, subsequently, for vascular remodeling.
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Salguero
authors.forename: Harald
authors.initials: H
authors.lastname: Schuett
authors.forename: Joanna
authors.initials: J
authors.lastname: Jagielska
authors.forename: René
authors.initials: R
authors.lastname: Schley
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Tallone
authors.forename: Maren
authors.initials: M
authors.lastname: Luchtefeld
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Karsten
authors.initials: K
authors.lastname: Grote
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
mesh_terms: D000818:Animals; D017536:Carotid Artery, Common / Q000502:physiology / Q000601:surgery*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050822:Cytokine Receptor gp130 / Q000172:deficiency*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D022781:Hepatocytes; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011336:Probability; D011897:Random Allocation; D012680:Sensitivity and Specificity; D000685:Serum Amyloid A Protein / Q000494:pharmacology*; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism; D017540:Tunica Media / Q000166:cytology / Q000378:metabolism
chemical_list: D000685:Serum Amyloid A Protein; D050822:Cytokine Receptor gp130