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Claus Oxvig

Effects of mutated pregnancy-associated plasma protein-a on atherosclerotic lesion development in mice

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  • Henning B Boldt, Denmark
  • Laurie K Bale, Division of Endocrinology and Metabolism (H.B.B., L.K.B., Z.T.R., C.A.C.), Endocrine Research Unit, Mayo Clinic, Rochester, United States
  • Zachary T Resch, Division of Endocrinology and Metabolism (H.B.B., L.K.B., Z.T.R., C.A.C.), Endocrine Research Unit, Mayo Clinic, Rochester, United States
  • Claus Oxvig
  • Michael Toft Overgaard, Department of Biotechnology, Chemistry, and Environmental Engineering (M.T.O.), Aalborg University, Denmark
  • Cheryl A. Conover, Division of Endocrinology and Metabolism (H.B.B., L.K.B., Z.T.R., C.A.C.), Endocrine Research Unit, Mayo Clinic, United States
Pregnancy-associated plasma protein-A (PAPP-A) is a large multidomain metalloprotease involved in cleavage of IGF binding protein (IGFBP)-4 and -5 thereby causing release of bioactive IGF. Individual domains of PAPP-A have been characterized in vitro, including the metzincin proteolytic domain important for IGFBP proteolytic activity, short consensus repeats critical for cell surface association, and Lin-12/Notch repeat module demonstrated to determine IGFBP substrate specificity. To test the hypothesis that specific cleavage of IGFBP-4 by PAPP-A in close proximity to the cell surface is required for development of lesions in a murine model of atherosclerosis, the following PAPP-A transgenic (Tg) mice were generated: Tg(E483A), which lacks all PAPP-A proteolytic activity; Tg(D1499A), which selectively lacks proteolytic activity against IGFBP-4; and Tg(K1296A/K1316A), in which cell surface binding is compromised. Following cross-breeding with apolipoprotein E (ApoE) knockout (KO) mice, ApoE KO/Tg mice were fed a high-fat diet to promote aortic lesion development. Lesion area was increased 2-fold in aortas from ApoE KO/Tg wild-type compared with ApoE KO mice (P
Original languageEnglish
JournalEndocrinology
Volume154
Issue1
Pages (from-to)246-252
Number of pages7
ISSN0013-7227
DOIs
Publication statusPublished - Jan 2013

    Research areas

  • Animals, Aorta, Apolipoproteins E, Atherosclerosis, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Female, Insulin-Like Growth Factor Binding Protein 4, Male, Mice, Mice, Knockout, Mice, Transgenic, Myocytes, Smooth Muscle, Pregnancy-Associated Plasma Protein-A

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