Claus Oxvig

Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice

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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, 05.2016, p. 36-43.

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@article{562ebb712ba745b0a0e36ba553207360,
title = "Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice",
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.",
author = "Steffensen, {Lasse B} and Conover, {Cheryl A} and Bj{\o}rklund, {Martin M} and Thomas Ledet and Bentzon, {Jacob F} and Claus Oxvig",
note = "Copyright {\textcopyright} 2016 Elsevier Ireland Ltd. All rights reserved.",
year = "2016",
month = may,
doi = "10.1016/j.atherosclerosis.2016.02.026",
language = "English",
volume = "248",
pages = "36--43",
journal = "Atherosclerosis",
issn = "0021-9150",
publisher = "Elsevier Ireland Ltd.",

}

RIS

TY - JOUR

T1 - Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice

AU - Steffensen, Lasse B

AU - Conover, Cheryl A

AU - Bjørklund, Martin M

AU - Ledet, Thomas

AU - Bentzon, Jacob F

AU - Oxvig, Claus

N1 - Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

PY - 2016/5

Y1 - 2016/5

N2 - 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.

AB - 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.

U2 - 10.1016/j.atherosclerosis.2016.02.026

DO - 10.1016/j.atherosclerosis.2016.02.026

M3 - Journal article

C2 - 26983002

VL - 248

SP - 36

EP - 43

JO - Atherosclerosis

JF - Atherosclerosis

SN - 0021-9150

ER -