Lasse B Steffensen1, Cheryl A Conover2, Martin M Bjørklund3, Thomas Ledet3, Jacob F Bentzon3, Claus Oxvig4. 1. Department of Molecular Biology and Genetics, Aarhus University, Denmark. 2. Department of Internal Medicine, Endocrine Research Unit, Rochester, MN, USA. 3. Department of Clinical Medicine, Aarhus University, Denmark. 4. Department of Molecular Biology and Genetics, Aarhus University, Denmark. Electronic address: co@mbg.au.dk.
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.
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-deficientmice 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: Sara Dam Kobberø; Michael Gajhede; Osman Asghar Mirza; Søren Kløverpris; Troels Rønn Kjær; Jakob Hauge Mikkelsen; Thomas Boesen; Claus Oxvig Journal: Nat Commun Date: 2022-10-18 Impact factor: 17.694
Authors: Germán Cediel; Ferran Rueda; Claus Oxvig; Teresa Oliveras; Carlos Labata; Oriol de Diego; Marc Ferrer; M Cruz Aranda-Nevado; Judith Serra-Gregori; Julio Núñez; Cosme García; Antoni Bayes-Genis Journal: Cardiovasc Diabetol Date: 2018-04-30 Impact factor: 9.951