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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

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