Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice

Lasse B. Steffensen, Cheryl A Conover, Martin M. Bjørklund, Thomas Ledet, Jacob F. Bentzon, Claus Oxvig

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background and aim: 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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)36-43
Number of pages8
JournalAtherosclerosis
Volume248
DOIs
StatePublished - May 1 2016

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Pregnancy-Associated Plasma Protein-A
Atherosclerosis
teleocalcin
Dependovirus
Aptitude
Human Development
Metalloproteases
Apolipoproteins E
Somatomedins
Atherosclerotic Plaques
Vascular Diseases
Smooth Muscle Myocytes
Aorta
Theoretical Models
Arteries
Immunohistochemistry

Keywords

  • Apolipoprotein E-deficient mice
  • Atherosclerosis
  • Pregnancy-associated plasma protein-A
  • Proteolytic inhibition
  • Stanniocalcin-2

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice. / Steffensen, Lasse B.; Conover, Cheryl A; Bjørklund, Martin M.; Ledet, Thomas; Bentzon, Jacob F.; Oxvig, Claus.

In: Atherosclerosis, Vol. 248, 01.05.2016, p. 36-43.

Research output: Contribution to journalArticle

Steffensen, Lasse B. ; Conover, Cheryl A ; Bjørklund, Martin M. ; Ledet, Thomas ; Bentzon, Jacob F. ; Oxvig, Claus. / Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice. In: Atherosclerosis. 2016 ; Vol. 248. pp. 36-43.
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