PMID- 17510462
OWN - NLM
STAT- MEDLINE
DCOM- 20070705
LR  - 20131121
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Linking)
VI  - 100
IP  - 12
DP  - 2007 Jun 22
TI  - 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.
PG  - 1696-702
AB  - 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.
FAU - Harrington, Sean C
AU  - Harrington SC
AD  - Division of Division of Endocrinology, Metabolism, and Nutrition , Mayo Clinic 
      College of Medicine, Rochester, MN 55905, USA.
FAU - Simari, Robert D
AU  - Simari RD
FAU - Conover, Cheryl A
AU  - Conover CA
LA  - eng
GR  - HL74871/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20070517
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Apolipoproteins E)
RN  - 0 (Dietary Fats)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 3.4.24.- (Pregnancy-Associated Plasma Protein-A)
SB  - IM
MH  - Animals
MH  - Apolipoproteins E/*genetics/physiology
MH  - Atherosclerosis/*genetics/pathology/*physiopathology
MH  - Cholesterol/blood
MH  - Dietary Fats/*adverse effects
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Female
MH  - *Gene Deletion
MH  - Gene Expression
MH  - Genetic Predisposition to Disease
MH  - Genotype
MH  - Insulin-Like Growth Factor I/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Pregnancy-Associated Plasma Protein-A/*genetics/*physiology
EDAT- 2007/05/19 09:00
MHDA- 2007/07/06 09:00
CRDT- 2007/05/19 09:00
PHST- 2007/05/19 09:00 [pubmed]
PHST- 2007/07/06 09:00 [medline]
PHST- 2007/05/19 09:00 [entrez]
AID - CIRCRESAHA.106.146183 [pii]
AID - 10.1161/CIRCRESAHA.106.146183 [doi]
PST - ppublish
SO  - Circ Res. 2007 Jun 22;100(12):1696-702. doi: 10.1161/CIRCRESAHA.106.146183. Epub 
      2007 May 17.