Interleukin-18 enhances vascular calcification and osteogenic differentiation of vascular smooth muscle cells through TRPM7 channel activation

Zhang, K., Zhang, Y., Feng, W., Chen, R., Chen, J., Touyz, R. M. , Wang, J. and Huang, H. (2017) Interleukin-18 enhances vascular calcification and osteogenic differentiation of vascular smooth muscle cells through TRPM7 channel activation. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(10), pp. 1933-1943. (doi: 10.1161/ATVBAHA.117.309161) (PMID:28860220)

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Abstract

Objective—Vascular calcification (VC) is an important predictor of cardiovascular morbidity and mortality. Osteogenic differentiation of vascular smooth muscle cells (VSMCs) is a key mechanism of VC. Recent studies show that IL-18 (interleukin-18) favors VC while TRPM7 (transient receptor potential melastatin 7) channel upregulation inhibits VC. However, the relationship between IL-18 and TRPM7 is unclear. We questioned whether IL-18 enhances VC and osteogenic differentiation of VSMCs through TRPM7 channel activation. Approach and Results—Coronary artery calcification and serum IL-18 were measured in patients by computed tomographic scanning and enzyme-linked immunosorbent assay, respectively. Primary rat VSMCs calcification were induced by high inorganic phosphate and exposed to IL-18. VSMCs were also treated with TRPM7 antagonist 2-aminoethoxy-diphenylborate or TRPM7 small interfering RNA to block TRPM7 channel activity and expression. TRPM7 currents were recorded by patch-clamp. Human studies showed that serum IL-18 levels were positively associated with coronary artery calcium scores (r=0.91; P<0.001). In VSMCs, IL-18 significantly decreased expression of contractile markers α-smooth muscle actin, smooth muscle 22 α, and increased calcium deposition, alkaline phosphatase activity, and expression of osteogenic differentiation markers bone morphogenetic protein-2, Runx2, and osteocalcin (P<0.05). IL-18 increased TRPM7 expression through ERK1/2 signaling activation, and TRPM7 currents were augmented by IL-18 treatment. Inhibition of TRPM7 channel by 2-aminoethoxy-diphenylborate or TRPM7 small interfering RNA prevented IL-18–enhanced osteogenic differentiation and VSMCs calcification. Conclusions—These findings suggest that coronary artery calcification is associated with increased IL-18 levels. IL-18 enhances VSMCs osteogenic differentiation and subsequent VC induced by β-glycerophosphate via TRPM7 channel activation. Accordingly, IL-18 may contribute to VC in proinflammatory conditions.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Touyz, Professor Rhian
Authors: Zhang, K., Zhang, Y., Feng, W., Chen, R., Chen, J., Touyz, R. M., Wang, J., and Huang, H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher:American Heart Association
ISSN:1079-5642
ISSN (Online):1524-4636
Published Online:31 August 2017
Copyright Holders:Copyright © 2017 American Heart Association, Inc.
First Published:First published in Arteriosclerosis, Thrombosis, and Vascular Biology 37(10): 1933-1943
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
607381Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762RI CARDIOVASCULAR & MEDICAL SCIENCES