High-phosphate induced vascular calcification is reduced by iron citrate through inhibition of extracellular matrix osteo-chondrogenic shift in VSMCs.
Animals
Cell Culture Techniques
Cell Differentiation
Chondrocytes
/ drug effects
Citric Acid
/ pharmacology
Extracellular Matrix
/ drug effects
Hyperphosphatemia
/ complications
Iron Compounds
/ pharmacology
Muscle, Smooth, Vascular
/ drug effects
Myocytes, Smooth Muscle
/ drug effects
Osteoblasts
/ drug effects
Rats
Vascular Calcification
/ etiology
Extracellular matrix
Iron
Phosphate
VSMC
Vascular calcification
Journal
International journal of cardiology
ISSN: 1874-1754
Titre abrégé: Int J Cardiol
Pays: Netherlands
ID NLM: 8200291
Informations de publication
Date de publication:
15 12 2019
15 12 2019
Historique:
received:
15
05
2019
revised:
16
08
2019
accepted:
25
09
2019
pubmed:
18
10
2019
medline:
11
7
2020
entrez:
18
10
2019
Statut:
ppublish
Résumé
High serum phosphate (Pi) levels strongly associate with cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients with vascular calcification playing a major role in the pathogenesis of related cardiovascular disease. High-Pi challenged vascular smooth muscle cells (VSMCs) undergo simil-osteoblastic transformation and actively deposit calcium-phosphate crystals. Iron-based Pi-binders are used to treat hyperphosphatemia in CKD patients. In this study, we investigated the direct effect of iron citrate on extracellular matrix (ECM) modification induced by high-Pi, following either prophylactic or therapeutic approach. Iron prophylactically prevents and therapeutically blocks high-Pi induced calcification. Masson's staining highlights the changes of muscular ECM that after high-Pi stimulation becomes fibrotic and which modifications are prevented or partially reverted by iron. Interestingly, iron preserves glycogen granules and either prevents or partially reverts the formation of non-glycogen granules induced by high-Pi. In parallel, iron addition is able to either prevent or block the high-Pi induced acid mucin deposition. Iron inhibited calcification also by preventing exosome osteo-chondrogenic shift by reducing phosphate load (0,61 ± 0.04vs0,45 ± 0.05, PivsPi + Fe, p < 0,05, nmol Pi/mg protein) and inducing miRNA 30c (0.62 ± 0.05vs3.07 ± 0.62; PivsPi + Fe, p < 0.01, relative expression). Studying aortic rings, we found that iron significantly either prevents or reverts the high-Pi induced collagen deposition and the elastin decrease, preserving elastin structure (0.7 ± 0.1 vs 1.2 ± 0.1; Pi vs Pi + Fe, p < 0.05, elastin mRNA relative expression). Iron directly either prevents or partially reverts the high-Pi induced osteo-chondrocytic shift of ECM. The protection of muscular nature of VSMC ECM may be one of the mechanisms elucidating the anti-calcific effect of iron.
Sections du résumé
BACKGROUND
High serum phosphate (Pi) levels strongly associate with cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients with vascular calcification playing a major role in the pathogenesis of related cardiovascular disease. High-Pi challenged vascular smooth muscle cells (VSMCs) undergo simil-osteoblastic transformation and actively deposit calcium-phosphate crystals. Iron-based Pi-binders are used to treat hyperphosphatemia in CKD patients.
METHODS
In this study, we investigated the direct effect of iron citrate on extracellular matrix (ECM) modification induced by high-Pi, following either prophylactic or therapeutic approach.
RESULTS
Iron prophylactically prevents and therapeutically blocks high-Pi induced calcification. Masson's staining highlights the changes of muscular ECM that after high-Pi stimulation becomes fibrotic and which modifications are prevented or partially reverted by iron. Interestingly, iron preserves glycogen granules and either prevents or partially reverts the formation of non-glycogen granules induced by high-Pi. In parallel, iron addition is able to either prevent or block the high-Pi induced acid mucin deposition. Iron inhibited calcification also by preventing exosome osteo-chondrogenic shift by reducing phosphate load (0,61 ± 0.04vs0,45 ± 0.05, PivsPi + Fe, p < 0,05, nmol Pi/mg protein) and inducing miRNA 30c (0.62 ± 0.05vs3.07 ± 0.62; PivsPi + Fe, p < 0.01, relative expression). Studying aortic rings, we found that iron significantly either prevents or reverts the high-Pi induced collagen deposition and the elastin decrease, preserving elastin structure (0.7 ± 0.1 vs 1.2 ± 0.1; Pi vs Pi + Fe, p < 0.05, elastin mRNA relative expression).
CONCLUSIONS
Iron directly either prevents or partially reverts the high-Pi induced osteo-chondrocytic shift of ECM. The protection of muscular nature of VSMC ECM may be one of the mechanisms elucidating the anti-calcific effect of iron.
Identifiants
pubmed: 31619363
pii: S0167-5273(19)32387-3
doi: 10.1016/j.ijcard.2019.09.068
pii:
doi:
Substances chimiques
Iron Compounds
0
Citric Acid
2968PHW8QP
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
94-103Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.