The pathogenic role of tumor necrosis factor superfamily ligands in atherogenesis and plaque destabilization
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AbstractThe aim of this thesis was to identify novel inflammatory mediators potentially contributing to plaque destabilization focusing on members of the tumor necrosis factor superfamily (TNFSF). 40 patients with stable angina, 40 patients with unstable angina and 20 healthy controls were investigated. Plasma levels of APRIL, LIGHT and OPG, all members of the TNFSF, was significantly raised in angina patients relative to controls with particularly high levels in unstable disease. Further studies pointed out T cells and/or monocytes as possible sources for the raised plasma levels of these mediators, and for APRIL, activated platelets seem to be the major contributor. To elucidate potential pathogenic effects of these TNFSF members, in vitro experiments were performed on cells with relevance to atherogenesis, revealing several pro-atherogenic effects, such as enhanced lipid accumulation in macrophages, inflammatory responses in endothelial cells, enhanced matrix degrading potential in vascular smooth muscle cells, and increased expression of pro-thrombotic mediators in macrophages. Immunostaining localized these TNFSF members to atherosclerotic plaques, supporting their atherogenic contribution.
List of papers
Paper I:Wiggo J. Sandberg, Arne Yndestad, Erik Øie, MD, Camilla Smith, Thor Ueland, Olga Ovchinnikova, Anna-Karin L. Robertson, Fredrik Müller, MD, Anne G. Semb, MD, Hanne Scholz, Arne K. Andreassen, Lars Gullestad, Jan Kristian Damås, Stig S. Frøland, MD, Göran K. Hansson, Bente Halvorsen, Pål Aukrust. Enhanced T-cell expression of RANK ligand in acute coronary syndrome – possible role in plaque progression Arteriosclerosis Thrombosis and Vascular Biology 2006 Apr;26(4):857-63Referansen
Paper II: Hanne Scholz, Wiggo Sandberg, Jan Kristian Damås, Camilla Smith, Arne K. Andreassen, Lars Gullestad, Stig S. Frøland, Arne Yndestad, Pål Aukrust, Bente Halvorsen. Enhanced plasma levels of LIGHT in Unstable Angina: Possible pathogenic role in foam cell formation and thrombosis Circulation 2005 Oct 4;112(14):2121-9.
Paper III: Wiggo J. Sandberg, Bente Halvorsen, Arne Yndestad, Camilla Smith, Kari Otterdal, Frank R. Brosstad, Stig S. Frøland, Peder S. Olofsson, Jan K. Damås, Lars Gullestad, Göran K. Hansson, Erik Øie, Pål Aukrust. Inflammatory interaction between LIGHT and Proteinase-activated receptor-2 in endothelial cells – potential role in atherogenesis Submitted. (Revised version accepted in Circulation Research)
Paper IV: Wiggo J. Sandberg, Kari Otterdal, Lars Gullestad, MD, Bente Halvorsen, Asgrimur Ragnarsson, Stig S. Frøland, Jan K. Damås, Erik Øie, Pål Aukrust, Gøran K. Hansson, Arne Yndestad.Platelets release the tumor necrosis factor superfamily ligand APRIL (TNFSF13) upon activation – increased expression of APRIL in coronary and carotid atherosclerosis Submitted.Referansen