Background: Vascular calcification is implicated in severe pathologies such as atherosclerosis and chronic kidney disease. Early-stage calcification (microcalcification) is considered to be life-threatening both by increasing risk of plaque rupture and evading detection by conventional imaging techniques. In addition, no therapy exists to intervene with ectopic calcification. Calcium binding properties of coagulation factors are governed by post-translationally modified γ-carboxy glutamic acid (Gla) residues, hence the Gla-domain. Previous research has shown that some of these Gla-domains are able to interact with deleterious calcium-crystal formation. The Gla-domain of protein S harbours the most Gla-residues of all vitamin K-dependent proteins.

Aims: To investigate if protein S Gla-domain can act as both tracer and therapy for microcalcification.

Methods: Protein S Gla domain was chemically synthesized and subsequently used for detection and inhibition of calcification in in vitro calcification assays. For this purpose, human vascular smooth muscle cells (hVSMCs) cultured under calcifying conditions were exposed to protein S Gla domain or a negative control protein S Glu domain. The ability to detect and interfere with calcification was determined using a combination of fluorescence microscopy and quantitative calcium phosphate crystal measurements.

Results: Protein S Gla domain selectively bound to microcalcifications in an in vitro setting allowing specific detection. Importantly, protein S Gla-domain interfered with initiation as well as progression of calcification of hVSMCs. Finally, at low concentrations, protein S Gla domain was used to follow progression of calcification in a time-dependent manner without interfering with the calcification process.

Conclusions: Protein S Gla-domain is a promising tool for detection and follow-up of early vascular calcification and has potential as a calcification inhibitor, due to its ability to interfere with calcification nucleation sites as well as progression of calcium crystals.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/protein-s-gla-domain-as-theranostic-for-early-vascular-calcification/