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Tumor necrosis factor-α plays an important role in restenosis development

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Author: Monraats, P.S. · Pires, N.M.M. · Schepers, A. · Agema, W.R.P. · Boesten, L.S.M. · Vries, M.R. de · Zwinderman, A.H. · Maat, M.P.M. de · Doevendans, P.A.F.M. · Winter, R.J. de · Tio, R.A. · Waltenberger, J. · Hart, L.M. 't · Frants, R.R. · Quax, P.H.A. · Vlijmen, B.J.M. van · Havekes, L.M. · Laarse, A. van der · Wall, E.E. van der · Jukema, J.W.
Institution: TNO Kwaliteit van Leven
Source:FASEB Journal, 14, 19, 1998-2004
Identifier: 238864
doi: doi:10.1096/fj.05-4634com
Keywords: Biology Health · Biomedical Research · Haplotype · TNFα · Transgenic mice · Apolipoprotein E3 · Messenger RNA · Thalidomide · Tumor necrosis factor alpha · Adult · Aged · Angiography · Animal experiment · Animal model · Clinical practice · Disease marker · Drug delivery system · Genetic polymorphism · Heredity · Knockout mouse · Nonhuman · Percutaneous coronary intervention · Restenosis · Risk assessment · Screening · Aged · Alleles · Angina Pectoris · Angiography · Angioplasty, Transluminal, Percutaneous Coronary · Animals · Constriction, Pathologic · Coronary Angiography · Coronary Disease · Coronary Restenosis · Disease Models, Animal · Female · Femoral Artery · Gene Expression Regulation, Neoplastic · Genetic Predisposition to Disease · Genotype · Haplotypes · Humans · Inflammation · Ischemia · Linkage Disequilibrium · Male · Mice · Mice, Knockout · Mice, Transgenic · Middle Aged · Multivariate Analysis · Odds Ratio · Polymorphism, Genetic · Regression Analysis · Reverse Transcriptase Polymerase Chain Reaction · Risk Factors · RNA, Messenger · Thalidomide · Treatment Outcome · Tumor Necrosis Factor-alpha · Up-Regulation · Animalia · Mus musculus


Genetic factors appear to be important in the restenotic process after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. TNFα, a key regulator of inflammatory responses, may exert critical influence on the development of restenosis after PCI. The GENetic DEterminants of Restenosis (GENDER) project included 3104 patients who underwent a successful PCI. Systematic genotyping for six polymorphisms in the TNFα gene was performed. The role of TNFα in restenosis was also assessed in ApoE*3-Leiden mice, TNFα knockout mice, and by local delivery of a TNFα biosynthesis inhibitor, thalidomide. The -238G-1031T haplotype of the TNFα gene increased clinical and angiographic risk of restenosis (P=0.02 and P=0.002, respectively). In a mouse model of reactive stenosis, arterial TNFα mRNA was significantly time-dependently up-regulated. Mice lacking TNFα or treated locally with thalidomide showed a reduction in reactive stenosis (P=0.01 and P=0.005, respectively). Clinical and preclinical data indicate that TNFα plays an important role in restenosis. Therefore, TNFα genotype may be used as a risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice. Inhibition of TNFα may be an anti-restenotic target strategy. ©FASEB. Chemicals / CAS: thalidomide, 50-35-1; RNA, Messenger; Thalidomide, 50-35-1; Tumor Necrosis Factor-alpha