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

TY - JOUR

T1 - Effects of mutated pregnancy-associated plasma protein-a on atherosclerotic lesion development in mice

AU - Boldt, Henning B

AU - Bale, Laurie K

AU - Resch, Zachary T

AU - Oxvig, Claus

AU - Overgaard, Michael Toft

AU - Conover, Cheryl A.

PY - 2013/1

Y1 - 2013/1

N2 - 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

AB - 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

KW - Animals

KW - Aorta

KW - Apolipoproteins E

KW - Atherosclerosis

KW - Cells, Cultured

KW - Enzyme-Linked Immunosorbent Assay

KW - Female

KW - Insulin-Like Growth Factor Binding Protein 4

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Myocytes, Smooth Muscle

KW - Pregnancy-Associated Plasma Protein-A

U2 - 10.1210/en.2012-1552

DO - 10.1210/en.2012-1552

M3 - Journal article

C2 - 23161866

SN - 0013-7227

VL - 154

SP - 246

EP - 252

JO - Endocrinology

JF - Endocrinology

IS - 1

ER -