Calcification stimulates inflammatory signalling pathways in human vascular smooth muscle cells

Proudfoot, D.; Dautova, Y.; Kozlova, D.; Epple, M. and Bootman, M. D. (2016). Calcification stimulates inflammatory signalling pathways in human vascular smooth muscle cells. In: Atherosclerosis, 244 e9-e10.

DOI: https://doi.org/10.1016/j.atherosclerosis.2015.10.078

Abstract

Introduction: Calcification is associated with ageing blood vessels and with diseases including atherosclerosis and osteoarthritis. In particular, small calcified particles correlate with atherosclerotic plaque instability and the reason for this is unknown. Some studies suggest that calcium phosphate (CaP) particles cause mechanical stress in the fibrous cap, while others imply that CaP can be engulfed by macrophages leading to caspase-1 activation and secretion of mature IL-1β. Our own studies suggest that small CaP particles are taken up into vascular smooth muscle cell (VSMC) and can cause cell death.
Methods: In this study, the effects of CaP particles on VSMC inflammatory pathway activity was investigated by Western analysis for caspase-1 and Syk, and for IL-1β release by ELISA.
Results: We found that CaP particles stimulated the secretion of IL-1β from growing and senescent human VSMCs, with higher levels of IL-1β release seen in senescent cells (up to 1.5ng/ml). IL-1β secretion required caspase-1 activity, but unlike macrophages, priming of cells was not required. IL-1β secretion was blocked by R406, a highly specific inhibitor of the Syk tyrosine kinase. Syk is known to be required for NLRP3 inflammasome activation, and Western blot analysis demonstrated that CaP particles induced Syk phosphorylation after 10 minutes of exposure to VSMCs. Additionally, inhibitors of particle uptake, wortmannin and chlorpromazine reduced CaP particle-induced IL-1β release.
Conclusions: Together, these studies indicate that CaP particles enter cells via endocytic mechanisms and activate Syk kinase and caspase-1 upstream of IL-1β release, and highlight that VSMCs have the potential to generate pro-inflammatory signals.

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