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

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1696-1702
Number of pages7
JournalCirculation research
Volume100
Issue number12
DOIs
StatePublished - Jun 1 2007

Keywords

  • Apolipoprotein E-deficient mice
  • Atherosclerosis
  • Insulin-like growth factor-I
  • Pregnancy-associated plasma protein-A

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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