Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA361

Poster Communications

Interleukin-18 promotes osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells through SGK1

N. Schelski1, T. Luong1, B. Pieske1,2,3, F. Lang4, J. Voelkl1, I. Alesutan1,2

1. Center for Cardiovascular Research Cardiology CVK, Charité - Universitätsmedizin Berlin, Berlin, Germany. 2. Berlin Institute of Health, Berlin, Germany. 3. Department of Internal Medicine and Cardiology, DHZB, Berlin, Germany. 4. Department of Physiology I, Eberhard-Karls University, Berlin, Germany.


Background: Increased interleukin-18 (IL-18) levels are associated with vascular smooth muscle cell (VSMC) osteo-/chondrogenic transdifferentiation and subsequent vascular calcification, but the underlying mechanisms are, however, still elusive. The present study explored the possible involvement of the serum- and glucocorticoid-inducible kinase 1 (SGK1), a key regulator of osteo-/chondrogenic transdifferentiation of VSMCs, in IL-18-induced vascular calcification. Methods: Experiments were performed in primary human aortic smooth muscle cells (HAoSMCs) following treatment with recombinant human IL-18 protein in the presence or absence of β-glycerophosphate, following SGK1 knockdown by silencing or pharmacological inhibition of the PI3K. The mRNA expression was analyzed by using quantitative RT-PCR, ALPL activity by a colorimetric method and calcification by Alizarin Red staining and calcium assay. Results: SGK1 mRNA expression was up-regulated in HAoSMCs by IL-18 treatment in a concentration-dependent manner, effects reaching statistical significance at 10 ng/ml IL-18 concentration. These effects were paralleled by a dose-dependent increase in osteogenic markers MSX2, CBFA1 and ALPL mRNA expression in IL-18 treated HAoSMCs. Moreover, phosphate-induced SGK1 and osteogenic markers mRNA expression and, thus, osteo-/chondrogenic transdifferentiation of HAoSMCs were further augmented in the presence of IL-18 in the cell culture medium. In accordance, IL-18 aggravated phosphate-induced calcification of HAoSMCs. Silencing of SGK1 blunted IL-18-induced expression of osteogenic markers MSX2, CBFA1 and ALPL mRNA in HAoSMCs as compared to negative control silenced HAoSMCs. The effects of IL-18 on SGK1 expression were suppressed in the presence of PI3K inhibitors LY294002 or wortmannin. Conclusions: IL-18 up-regulates SGK1 in VSMCs and SGK1 participates in the intracellular signaling of IL-18-induced osteo-/chondrogenic transdifferentiation of VSMCs.

Where applicable, experiments conform with Society ethical requirements