This Article Free upon publication Full Text Full Text (PDF) Data Supplement All Versions of this Article: 100/12/1696    most recent CIRCRESAHA.106.146183v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Harrington, S. C. Articles by Conover, C. A. Search for Related Content PubMed PubMed Citation Articles by Harrington, S. C. Articles by Conover, C. A. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL Medline Plus Health Information Dietary Fats Related Collections Animal models of human disease Genetically altered mice Growth factors/cytokines

(Circulation Research. 2007;100:1696.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Genetic Deletion of Pregnancy-Associated Plasma Protein-A Is Associated With Resistance to Atherosclerotic Lesion Development in Apolipoprotein E–Deficient Mice Challenged With a High-Fat Diet

Sean C. Harrington, Robert D. Simari, Cheryl A. Conover

From the Division of Division of Endocrinology, Metabolism, and Nutrition (A.C.H., C.A.C.) and the Division of Cardiovascular Diseases (R.D.S.), Mayo Clinic College of Medicine, Rochester, Minn.

Correspondence to Cheryl A. Conover, PhD, Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, MN 55905. E-mail Conover.Cheryl{at}Mayo.edu

Pregnancy-associated plasma protein–A (PAPP-A), a metalloproteinase in the insulin-like growth factor (IGF) system, is markedly upregulated in human atherosclerotic plaque. To determine whether PAPP-A plays an active role in the development of atherosclerosis, we crossed mice lacking apolipoprotein E (ApoE) with PAPP-A–deficient mice, generating ApoE knock-out (KO), PAPP-A KO, wild-type (WT/WT), and ApoE/PAPP-A double KO (KO/KO) mice. These mice were fed a high-fat diet starting at 7 weeks of age. Total serum cholesterol levels were elevated similarly in the ApoE KO and KO/KO mice and were 10-fold higher than in the WT/WT and PAPP-A KO mice. WT/WT and PAPP-A KO mice showed little or no lesion development even after 20 weeks of diet. ApoE KO mice had a progressive increase in aortic lesion area over 20 weeks of diet. In comparison, lesion area was reduced 60% to 80% in KO/KO mice. Lesions of ApoE KO aortas had 8- to 20-fold increases in PAPP-A, IGFBP-4, and IGF-I mRNA levels compared with nonlesional areas, whereas IGF-I receptor levels were equivalent—conditions for enhanced lesional IGF activity. Consistent with this, an in vivo marker of IGF-I receptor-mediated action was increased 10-fold in lesions from ApoE KO compared with KO/KO aortas. These data indicate that PAPP-A plays a critical role in lesion development in a mouse model of atherosclerosis, at least in part, through amplification of local IGF-I bioavailability.

Key Words: pregnancy-associated plasma protein-A • apolipoprotein E-deficient mice • atherosclerosis • insulin-like growth factor-I

This article has been cited by other articles:

				S. Horng, G. Kreiman, C. Ellsworth, D. Page, M. Blank, K. Millen, and M. Sur Differential Gene Expression in the Developing Lateral Geniculate Nucleus and Medial Geniculate Nucleus Reveals Novel Roles for Zic4 and Foxp2 in Visual and Auditory Pathway Development J. Neurosci., October 28, 2009; 29(43): 13672 - 13683. [Abstract] [Full Text] [PDF]

				C. Ohlsson, S. Mohan, K. Sjogren, A. Tivesten, J. Isgaard, O. Isaksson, J.-O. Jansson, and J. Svensson The Role of Liver-Derived Insulin-Like Growth Factor-I Endocr. Rev., August 1, 2009; 30(5): 494 - 535. [Abstract] [Full Text] [PDF]

				A. N. Vallejo, J. J. Michel, L. K. Bale, B. H. Lemster, L. Borghesi, and C. A. Conover Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A PNAS, July 7, 2009; 106(27): 11252 - 11257. [Abstract] [Full Text] [PDF]

				L. A. Maile, B. E. Capps, E. C. Miller, A. W. Aday, and D. R. Clemmons Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo Diabetes, October 1, 2008; 57(10): 2637 - 2643. [Abstract] [Full Text] [PDF]

				J. H. Mikkelsen, C. Gyrup, P. Kristensen, M. T. Overgaard, C. B. Poulsen, L. S. Laursen, and C. Oxvig Inhibition of the Proteolytic Activity of Pregnancy-associated Plasma Protein-A by Targeting Substrate Exosite Binding J. Biol. Chem., June 13, 2008; 283(24): 16772 - 16780. [Abstract] [Full Text] [PDF]