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

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  • Henning B Boldt, Danmark
  • 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, USA
  • 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, USA
  • Claus Oxvig
  • Michael Toft Overgaard, Department of Biotechnology, Chemistry, and Environmental Engineering (M.T.O.), Aalborg University, Danmark
  • 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, USA
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
OriginalsprogEngelsk
TidsskriftEndocrinology
Vol/bind154
Nummer1
Sider (fra-til)246-252
Antal sider7
ISSN0013-7227
DOI
StatusUdgivet - jan. 2013

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