Interleukin-18 Enhances Vascular Calcification and Osteogenic Differentiation of Vascular Smooth Muscle Cells Through TRPM7 Activation

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 37; no. 10; pp. 1933 - 1943
• Main Authors: Zhang, Kun, Zhang, Yinyin, Feng, Weijing, Chen, Renhua, Chen, Jie, Touyz, Rhian M, Wang, Jingfeng, Huang, Hui
• Format: Journal Article
• Language: English
• Published: United States 01-10-2017
• Subjects: Cell Differentiation; Cells, Cultured; Humans; Interleukin-18 - blood; Interleukin-18 - physiology; MAP Kinase Signaling System - physiology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - physiology; Osteogenesis; Protein-Serine-Threonine Kinases - metabolism; TRPM Cation Channels - metabolism; Up-Regulation; Vascular Calcification - physiopathology; alkaline phosphatase; bone morphogenetic protein 2; RNA, small interfering; interleukin-18; vascular calcification
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.117.309161

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.
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 (
=0.91;
<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 (runt-related transcription factor 2), and osteocalcin (
<0.05). IL-18 increased TRPM7 expression through ERK1/2 (extracellular signal-regulated kinase 1/2) 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.
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.