Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice. (May 2016)

• Record Type: Journal Article
• Authors: Steffensen, Lasse B.; Conover, Cheryl A.; Bjørklund, Martin M.; Ledet, Thomas; Bentzon, Jacob F.; Oxvig, Claus
• Is Part Of: Atherosclerosis. Volume 248(2016)
• Page Start: 36
• Page End: 43
• Publication Date: 2016-05
• Subjects: Atherosclerosis -- Apolipoprotein E-deficient mice -- Stanniocalcin-2 -- Pregnancy-associated plasma protein-A -- Proteolytic inhibition; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2016.02.026
• Languages: English
• ISSNs: 0021-9150

Abstract

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. Highlights: Human SMCs secrete the proatherogenic proteinase PAPP-A and its novel inhibitor STC2. Extracts of human plaques contain both inhibited PAPP-A:STC2 complex and free PAPP-A. STC2 and PAPP-A are expressed in the tissue throughout human atherogenesis. Overexpression of STC2 reduces atherogenesis in hypercholesterolemic mice.