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

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.

• Authors: Henning B Boldt, Laurie K Bale, Zachary T Resch, Claus Oxvig, Michael T Overgaard, Cheryl A Conover
• Journal: Endocrinology (Endocrinology) Vol. 154 Issue 1 Pg. 246-52 (Jan 2013) ISSN: 1945-7170 [Electronic] United States
• PMID: 23161866 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Apolipoproteins E
• Insulin-Like Growth Factor Binding Protein 4
• Pregnancy-Associated Plasma Protein-A

Topics

• Animals
• Aorta (cytology)
• Apolipoproteins E (genetics, metabolism)
• Atherosclerosis (genetics, metabolism)
• 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, metabolism)