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Effects of mutated pregnancy-associated plasma protein-a on atherosclerotic lesion development in mice.
- Source :
-
Endocrinology [Endocrinology] 2013 Jan; Vol. 154 (1), pp. 246-52. Date of Electronic Publication: 2012 Nov 16. - Publication Year :
- 2013
-
Abstract
- 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 < 0.001). However, there was no significant increase in the lesion area in any of the ApoE KO/Tg mutant mice. We conclude that PAPP-A proteolytic activity is required for the lesion-promoting effect of PAPP-A and that its specificity must be directed against IGFBP-4. Furthermore, our data demonstrate that cleavage of IGFBP-4 at a distance from the cell surface, and hence from the IGF receptor, is not effective in promoting the development of the atherosclerotic lesions. Thus, PAPP-A exerts its effect while bound to the cell surface in vivo.
- Subjects :
- Animals
Aorta cytology
Apolipoproteins E genetics
Apolipoproteins E metabolism
Atherosclerosis genetics
Cells, Cultured
Enzyme-Linked Immunosorbent Assay
Female
Insulin-Like Growth Factor Binding Protein 4 metabolism
Male
Mice
Mice, Knockout
Mice, Transgenic
Myocytes, Smooth Muscle metabolism
Pregnancy-Associated Plasma Protein-A genetics
Atherosclerosis metabolism
Pregnancy-Associated Plasma Protein-A metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7170
- Volume :
- 154
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 23161866
- Full Text :
- https://doi.org/10.1210/en.2012-1552