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Osteogenic differentiation and calcification of human aortic smooth muscle cells is induced by the RCN2/STAT3/miR-155-5p feedback loop.

Abstract：

BACKGROUND:Vascular calcification (VC) is associated with the high morbidity and mortality of cardiovascular diseases in dialysis patients and is a process in which vascular smooth muscle cells (VSMCs) actively differentiate into osteoblast-like cells. Reticulocalbin-2 (RCN2) is involved in the process of osteogenic differentiation under diabetic conditions, but its regulatory role under hyperphosphatemic conditions and the related mechanisms remain unclear. In this study, the importance of the interactions among RCN2, STAT3 and miR-155-5p during the osteogenic differentiation and calcification of human aortic VSMCs (HASMCs) were investigated. METHODS:RCN2 was measured in femoropopliteal artery plaque specimens from 6 peripheral arterial disease (PAD) patients with chronic kidney disease (CKD) and 6 PAD patients without CKD. RCN2 protein and mRNA expression were assessed in the high phosphate-induced aortic rings culture ex vivo model. In vitro calcification assays and molecular mechanism studies were performed in HASMCs. RESULTS:Immunohistochemical staining results revealed increased RCN2 expression in the calcified plaques of femoral arteries of patients with CKD and in a high phosphate-induced aortic culture ex vivo model. RCN2 promoted HASMCs osteogenic differentiation and calcification by inducing STAT3 phosphorylation. Furthermore, inhibition of STAT3 activation by cryptotanshinone (CT) promoted miR-155-5p expression in HASMCs. In turn, miR-155-5p inhibited RCN2 mRNA expression, while RCN2 overexpression partially offset the miR-155-5p-mediated inhibition of HASMC calcification, acting as a positive feedback loop. CONCLUSION:These results demonstrate that RCN2 is a crucial regulator of VC under hyperphosphatemic conditions. RCN2/STAT3/miR-155-5p feedback loop is important in VC and targeting each member of this feedback loop could potentially reverse high phosphate-induced VC.

journal_name

Vascul Pharmacol

journal_title

Vascular pharmacology

authors

Zhao J,Liu Z,Chang Z

doi

10.1016/j.vph.2020.106821

subject

Has Abstract

pub_date

2021-02-01 00:00:00

pages

106821

eissn

1537-1891

issn

1879-3649

pii

S1537-1891(20)30326-8

journal_volume

136

pub_type

杂志文章

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Osteogenic differentiation and calcification of human aortic smooth muscle cells is induced by the RCN2/STAT3/miR-155-5p feedback loop.