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.
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.
Harrington
Sean C
SC
Division of Division of Endocrinology, Metabolism, and Nutrition , Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Simari
Robert D
RD
Conover
Cheryl A
CA
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000502:physiology; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D002784:Cholesterol / Q000097:blood; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005838:Genotype; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics* / Q000502:physiology*
D001057:Apolipoproteins E; D004041:Dietary Fats; D007334:Insulin-Like Growth Factor I; D002784:Cholesterol; D011266:Pregnancy-Associated Plasma Protein-A