title: Porcine complement regulators protect aortic smooth muscle cells poorly against human complement-induced lysis and proliferation: consequences for xenotransplantation.
abstract: BACKGROUND
  Accelerated atherosclerosis after transplantation has been observed and is characterized by smooth muscle cell proliferation in the graft. Porcine cells are frequently used in models of atherosclerosis and porcine organs are considered for use in transplantation. Complement (C) activation is known to play a major role in rejection of xenografts and is also considered to play a role in the development of atherosclerosis. The aim of this study was to investigate the expression and function of membrane bound regulators of complement (CReg) on porcine aortic smooth muscle cells (PASMC).
  
  
  METHODS
  The PASMC were assessed for expression of CReg and susceptibility to lysis by human C by flow-cytometry. The effect of various cytokines on CReg expression and C-susceptibility was investigated. The ability of human C to induce cell proliferation was assessed using the Alamar blue assay.
  
  
  RESULTS
  The PASMC only express the CReg membrane cofactor protein (MCP) and CD59 on their cell surface. MCP expression was increased by interleukin (IL)-4. In contrast to porcine aortic endothelial cells (PAEC), PASMC were found to be surprisingly sensitive to C-mediated lysis, mainly due to a low level of expression of CD59. Human C-induced proliferation of PASMC, which was dependent on complete membrane attack complex (MAC) formation.
  
  
  CONCLUSIONS
  Endogenously expressed CReg on PASMC poorly protect these cells to human C. Human C can induce proliferation of PASMC. In order to prevent accelerated atherosclerosis in porcine xenografts, increased levels of CReg not only have to be obtained on the endothelial cells but also on the smooth muscle cells.
authors.affiliation: Department of Pharmacology, Therapeutics and Toxicology, Wales Heart Research Institute, Cardiff University, Wales College of Medicine, Cardiff, CF144XN, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Capey
authors.forename: Carmen W
authors.initials: CW
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D018958:CD55 Antigens / Q000378:metabolism; D018957:CD59 Antigens / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D015938:Complement Membrane Attack Complex / Q000096:biosynthesis; D003165:Complement System Proteins / Q000502:physiology*; D019610:Cytoprotection; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013552:Swine / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C497857:CD46 protein, human; D018958:CD55 Antigens; D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D015847:Interleukin-4; D003165:Complement System Proteins