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

Kun Zhang; Yinyin Zhang; Weijing Feng; Renhua Chen; Jie Chen; Rhian M Touyz; Jingfeng Wang; Hui Huang

doi:10.1161/ATVBAHA.117.309161

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

Arterioscler Thromb Vasc Biol. 2017 Oct;37(10):1933-1943. doi: 10.1161/ATVBAHA.117.309161. Epub 2017 Aug 31.

Authors

Kun Zhang¹, Yinyin Zhang¹, Weijing Feng¹, Renhua Chen¹, Jie Chen¹, Rhian M Touyz¹, Jingfeng Wang², Hui Huang²

Affiliations

¹ From the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology (K.Z., Y.Z., W.F., R.C., J.W., H.H.) and Department of Radiation Oncology (J.C.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (K.Z., Y.Z., W.F., R.C., J.C., J.W., H.H.); and Institute of Cardiovascular and Medical Sciences, British Heart Foundation (BHF) Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom (R.M.T.).
² From the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology (K.Z., Y.Z., W.F., R.C., J.W., H.H.) and Department of Radiation Oncology (J.C.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (K.Z., Y.Z., W.F., R.C., J.C., J.W., H.H.); and Institute of Cardiovascular and Medical Sciences, British Heart Foundation (BHF) Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom (R.M.T.). huangh8@mail.sysu.edu.cn sysmwjf@163.com.

PMID: 28860220
DOI: 10.1161/ATVBAHA.117.309161

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 (runt-related transcription factor 2), and osteocalcin (P<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.

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.

Keywords: RNA, small interfering; alkaline phosphatase; bone morphogenetic protein 2; interleukin-18; vascular calcification.

MeSH terms

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*

Substances

Interleukin-18
TRPM Cation Channels
Protein Serine-Threonine Kinases
TRPM7 protein, human

Grants and funding

CH/4/29762/British Heart Foundation/United Kingdom