Targeting androgen receptor in macrophages inhibits phosphate-induced vascular smooth muscle cell calcification by decreasing IL-6 expression.
Actins
/ metabolism
Cell Transdifferentiation
/ drug effects
Core Binding Factor Alpha 1 Subunit
/ metabolism
Down-Regulation
Humans
Interleukin-6
/ genetics
Macrophages
/ metabolism
Muscle, Smooth, Vascular
/ drug effects
Myocytes, Smooth Muscle
/ drug effects
Osteoblasts
/ drug effects
Osteogenesis
/ drug effects
Paracrine Communication
Phosphates
/ toxicity
Receptors, Androgen
/ genetics
Signal Transduction
THP-1 Cells
Vascular Calcification
/ genetics
Androgen receptor
IL-6
Inflammation
Macrophage
Vascular calcification
Journal
Vascular pharmacology
ISSN: 1879-3649
Titre abrégé: Vascul Pharmacol
Pays: United States
ID NLM: 101130615
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
09
01
2020
revised:
24
04
2020
accepted:
03
05
2020
pubmed:
11
5
2020
medline:
22
10
2020
entrez:
11
5
2020
Statut:
ppublish
Résumé
Vascular calcification (VC) is a common complication of chronic kidney disease (CKD). However, its mechanisms remain unclear. VC, similar to atherosclerosis, is an inflammatory disease. Vascular smooth muscle cells (VSMCs) play a key role in VC progression. The androgen receptor (AR) in monocytes/macrophages plays an important role in inflammatory diseases. Here, we define the role of macrophage (MФ) AR in inorganic phosphate-induced VSMC calcification. Our results show that the conditioning medium (CM) of silencing AR in macrophages inhibits inorganic phosphate-induced human aortic smooth muscle cell (HASMC) calcification, and alleviates the transdifferentiation of HASMCs into osteoblasts for the protein expression of osteoblasts marker Runt-related transcription factor-2 (Runx2) in HASMCs decreased while that of smooth muscle cell marker SM22α increased. The effect of AR on HASMC calcification might mainly be mediated by the inflammatory cytokine IL-6. Silencing AR in monocytes/macrophages can dramatically decrease IL-6 expression. We also investigated how macrophage AR regulates IL-6. ChIP and luciferase assays indicate that AR directly binds to the ARE sequence in the promoter of the IL-6 gene to accelerate transcription and expression. To our knowledge, this is the first investigation that has established the correlation between AR and VC and identified the contribution of AR in the calcification of VSMCs. In addition, this study describes a novel target for therapeutic intervention in VC.
Identifiants
pubmed: 32387336
pii: S1537-1891(20)30004-5
doi: 10.1016/j.vph.2020.106681
pii:
doi:
Substances chimiques
ACTA2 protein, human
0
AR protein, human
0
Actins
0
Core Binding Factor Alpha 1 Subunit
0
IL6 protein, human
0
Interleukin-6
0
Phosphates
0
RUNX2 protein, human
0
Receptors, Androgen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
106681Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declared that they have no conflicts of interest to this work.