Lumenal calcification and microvasculopathy in fetuin-A-deficient mice lead to multiple organ morbidity.
Animals
Calcinosis
/ complications
Calcium
/ metabolism
Cardiovascular Diseases
/ genetics
Male
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Knockout
Microcirculation
/ physiology
Microvessels
/ metabolism
Minerals
/ metabolism
Mononuclear Phagocyte System
/ metabolism
Multiple Organ Failure
/ genetics
Vascular Calcification
/ genetics
alpha-2-HS-Glycoprotein
/ deficiency
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
30
09
2019
accepted:
16
01
2020
entrez:
20
2
2020
pubmed:
20
2
2020
medline:
7
5
2020
Statut:
epublish
Résumé
The plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles (CPP)-rapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore pathological mineralization (calcification). The mutant mouse strain D2,Ahsg-/- combines fetuin-A deficiency with the calcification-prone DBA/2 genetic background, having a particularly severe compound phenotype of microvascular and soft tissue calcification. Here we studied mechanisms leading to soft tissue calcification, organ damage and death in these mice. We analyzed mice longitudinally by echocardiography, X-ray-computed tomography, analytical electron microscopy, histology, mass spectrometry proteomics, and genome-wide microarray-based expression analyses of D2 wildtype and Ahsg-/- mice. Fetuin-A-deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature death. Importantly, early-stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood. Genome-wide expression analysis of calcified lesions and surrounding (not calcified) tissue, together with morphological observations, indicated that the calcification was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis. Collectively, these results demonstrate that soft tissue calcification can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of calcified matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis.
Identifiants
pubmed: 32074120
doi: 10.1371/journal.pone.0228503
pii: PONE-D-19-27423
pmc: PMC7029858
doi:
Substances chimiques
Ahsg protein, mouse
0
Minerals
0
alpha-2-HS-Glycoprotein
0
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0228503Subventions
Organisme : NIGMS NIH HHS
ID : P50 GM076547
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM087221
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027584
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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