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Chronic kidney disease circulating calciprotein particles and extracellular vesicles promote vascular calcification : a role for GRP (Gla-rich protein)

Carla SB Viegas, Lúcia Santos, Anjos L Macedo, António A Matos, Ana Sílvia Ferreira Diamantino Coelho e Silva UGent, Pedro L Neves, An Staes UGent, Kris Gevaert UGent, Rute Morais, Cees Vermeer, et al. (2018) ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY. 38(3). p.575-587
abstract
Objective: Inhibition of mineral crystal formation is a crucial step in ectopic calcification. Serum calciprotein particles (CPPs) have been linked to chronic kidney disease (CKD) calcification propensity, but additional knowledge is required to understand their function, assemblage, and composition. The role of other circulating nanostructures, such as extracellular vesicles (EVs) in vascular calcification is currently unknown. Here, we investigated the association of GRP (Gla-rich protein) with circulating CPP and EVs and the role of CKD CPPs and EVs in vascular calcification. Approach and Results: Biological CPPs and EVs were isolated from healthy and CKD patients and comparatively characterized using ultrastructural, analytic, molecular, and immuno-based techniques. Our results show that GRP is a constitutive component of circulating CPPs and EVs. CKD stage 5 serum CPPs and EVs are characterized by lower levels of fetuin-A and GRP, and CPPs CKD stage 5 have increased mineral maturation, resembling secondary CPP particles. Vascular smooth muscle cell calcification assays reveal that CPPs CKD stage 5 and EVs CKD stage 5 are taken up by vascular smooth muscle cells and induce vascular calcification by promoting cell osteochondrogenic differentiation and inflammation. These effects were rescued by incubation of CPPs CKD stage 5 with -carboxylated GRP. In vitro, formation and maturation of basic calcium phosphate crystals was highly reduced in the presence of -carboxylated GRP, fetuin-A, and MGP (matrix gla protein), and a similar antimineralization system was identified in vivo. Conclusions: Uremic CPPs and EVs are important players in the mechanisms of widespread calcification in CKD. We propose a major role for cGRP as inhibitory factor to prevent calcification at systemic and tissue levels.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
cardiovascular disease, extracellular vesicles, myocytes, smooth muscle, nanoparticle, renal insufficiency, chronic, vascular calcification, FETUIN-MINERAL COMPLEX, SMOOTH-MUSCLE-CELLS, CALCIUM-PHOSPHATE CRYSTALS, ARTERIAL CALCIFICATION, PREDIALYSIS CKD, MATRIX VESICLES, SERUM, OSTEOARTHRITIS, INFLAMMATION, INHIBITION
journal title
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Arterioscler. Thromb. Vasc. Biol.
volume
38
issue
3
pages
575 - 587
Web of Science type
Article
Web of Science id
000425754700014
ISSN
1079-5642
1524-4636
DOI
10.1161/atvbaha.117.310578
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8546524
handle
http://hdl.handle.net/1854/LU-8546524
date created
2018-01-29 11:22:09
date last changed
2018-04-05 09:01:35
@article{8546524,
  abstract     = {Objective: Inhibition of mineral crystal formation is a crucial step in ectopic calcification. Serum calciprotein particles (CPPs) have been linked to chronic kidney disease (CKD) calcification propensity, but additional knowledge is required to understand their function, assemblage, and composition. The role of other circulating nanostructures, such as extracellular vesicles (EVs) in vascular calcification is currently unknown. Here, we investigated the association of GRP (Gla-rich protein) with circulating CPP and EVs and the role of CKD CPPs and EVs in vascular calcification. 
Approach and Results: Biological CPPs and EVs were isolated from healthy and CKD patients and comparatively characterized using ultrastructural, analytic, molecular, and immuno-based techniques. Our results show that GRP is a constitutive component of circulating CPPs and EVs. CKD stage 5 serum CPPs and EVs are characterized by lower levels of fetuin-A and GRP, and CPPs CKD stage 5 have increased mineral maturation, resembling secondary CPP particles. Vascular smooth muscle cell calcification assays reveal that CPPs CKD stage 5 and EVs CKD stage 5 are taken up by vascular smooth muscle cells and induce vascular calcification by promoting cell osteochondrogenic differentiation and inflammation. These effects were rescued by incubation of CPPs CKD stage 5 with -carboxylated GRP. In vitro, formation and maturation of basic calcium phosphate crystals was highly reduced in the presence of -carboxylated GRP, fetuin-A, and MGP (matrix gla protein), and a similar antimineralization system was identified in vivo. 
Conclusions: Uremic CPPs and EVs are important players in the mechanisms of widespread calcification in CKD. We propose a major role for cGRP as inhibitory factor to prevent calcification at systemic and tissue levels.},
  author       = {Viegas, Carla SB and Santos, L{\'u}cia and Macedo, Anjos L and Matos, Ant{\'o}nio A and Ferreira Diamantino Coelho e Silva, Ana S{\'i}lvia and Neves, Pedro L and Staes, An and Gevaert, Kris and Morais, Rute and Vermeer, Cees and Schurgers, Leon and Simes, Dina C},
  issn         = {1079-5642},
  journal      = {ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY},
  keyword      = {cardiovascular disease,extracellular vesicles,myocytes,smooth muscle,nanoparticle,renal insufficiency,chronic,vascular calcification,FETUIN-MINERAL COMPLEX,SMOOTH-MUSCLE-CELLS,CALCIUM-PHOSPHATE CRYSTALS,ARTERIAL CALCIFICATION,PREDIALYSIS CKD,MATRIX VESICLES,SERUM,OSTEOARTHRITIS,INFLAMMATION,INHIBITION},
  language     = {eng},
  number       = {3},
  pages        = {575--587},
  title        = {Chronic kidney disease circulating calciprotein particles and extracellular vesicles promote vascular calcification : a role for GRP (Gla-rich protein)},
  url          = {http://dx.doi.org/10.1161/atvbaha.117.310578},
  volume       = {38},
  year         = {2018},
}

Chicago
Viegas, Carla SB, Lúcia Santos, Anjos L Macedo, António A Matos, Ana Sílvia Ferreira Diamantino Coelho e Silva, Pedro L Neves, An Staes, et al. 2018. “Chronic Kidney Disease Circulating Calciprotein Particles and Extracellular Vesicles Promote Vascular Calcification : a Role for GRP (Gla-rich Protein).” Arteriosclerosis Thrombosis and Vascular Biology 38 (3): 575–587.
APA
Viegas, C. S., Santos, L., Macedo, A. L., Matos, A. A., Ferreira Diamantino Coelho e Silva, A. S., Neves, P. L., Staes, A., et al. (2018). Chronic kidney disease circulating calciprotein particles and extracellular vesicles promote vascular calcification : a role for GRP (Gla-rich protein). ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 38(3), 575–587.
Vancouver
1.
Viegas CS, Santos L, Macedo AL, Matos AA, Ferreira Diamantino Coelho e Silva AS, Neves PL, et al. Chronic kidney disease circulating calciprotein particles and extracellular vesicles promote vascular calcification : a role for GRP (Gla-rich protein). ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY. 2018;38(3):575–87.
MLA
Viegas, Carla SB, Lúcia Santos, Anjos L Macedo, et al. “Chronic Kidney Disease Circulating Calciprotein Particles and Extracellular Vesicles Promote Vascular Calcification : a Role for GRP (Gla-rich Protein).” ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 38.3 (2018): 575–587. Print.