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(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

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