title: Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice.
abstract: OBJECTIVE
  The metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) has been suggested as a proatherogenic molecule by its ability to locally increase insulin-like growth factor signaling. Stanniocalcin-2 (STC2) was recently discovered to be a potent inhibitor of PAPP-A activity, but has not previously been implicated in vascular disease. The aim of this study was to substantiate the interaction between PAPP-A and STC2 as a potential local regulatory mechanism in the artery wall.
  
  
  RESULTS
  We found that PAPP-A is secreted from cultured primary smooth muscle cells obtained from human aortas as a covalent complex with STC2, devoid of proteolytic activity. Extracts of human carotid atherosclerotic plaques contain both complexed and uncomplexed PAPP-A, and we show by immunohistochemistry that PAPP-A and STC2 are present in the tissue throughout early human lesion development. We then used adeno-associated virus-mediated expression of STC2 to increase the fraction of PAPP-A present in the inhibited state and found that it decreased the development of atherosclerosis by 47% (P = 0.0005) in apolipoprotein E-deficient mice challenged with a Western type diet compared to controls.
  
  
  CONCLUSIONS
  This study is the first to suggest the involvement of STC2 in regulating PAPP-A activity during the development of atherosclerosis. Furthermore, we demonstrate that lesion development can be inhibited in an experimental model by driving the balance towards inhibited PAPP-A.
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Denmark.
authors.forename: Lasse B
authors.initials: LB
authors.lastname: Steffensen
authors.affiliation: Department of Internal Medicine, Endocrine Research Unit, Rochester, MN, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Conover
authors.affiliation: Department of Clinical Medicine, Aarhus University, Denmark.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Bjørklund
authors.affiliation: Department of Clinical Medicine, Aarhus University, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ledet
authors.affiliation: Department of Clinical Medicine, Aarhus University, Denmark.
authors.forename: Jacob F
authors.initials: JF
authors.lastname: Bentzon
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Denmark. Electronic address: co@mbg.au.dk.
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D001057:Apolipoproteins E / Q000235:genetics; D001158:Arteries / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C114997:STC2 protein, human; C485438:Stc2 protein, mouse; D011266:Pregnancy-Associated Plasma Protein-A
keywords: Apolipoprotein E-deficient mice; Atherosclerosis; Pregnancy-associated plasma protein-A; Proteolytic inhibition; Stanniocalcin-2