Abstract Number: PB0165
Meeting: ISTH 2022 Congress
Background: Early-stage calcification (microcalcification) progresses atherosclerosis and is often related to severe pathological outcomes such as myocardial infarction and stroke. The danger of microcalcification is two-fold in that it is undetectable with conventional imaging modalities, and no treatment currently exists to prevent or reduce it. An interesting source for development of new diagnostics and therapeutics against ectopic calcification is vitamin K-dependent Gla-domain of coagulation factors. These domains confer calcium ion-binding properties to coagulation factors via γ-carboxyglutamic acid (Gla) residues and have previously been shown to interact with ectopic calcium-crystals. We selected the protein S Gla-domain because of its 11 Gla-residues and previous evidence of its calcification inhibiting effect.
Aims: To investigate the application of protein S Gla-domain as tracer and treatment of microcalcification.
Methods: Protein S Gla-domain (fully carboxylated) and negative control protein S Glu-domain (uncarboxylated) were chemically synthesized and assessed for calcification inhibition and detection in non-cellular crystallisation assays and primary human vascular smooth muscle cell (hVSMC)-based calcification assays. Protein S Gla-domain was also tested for ex vivo detection of microcalcification in atherosclerotic lesions of high-fat diet fed ApoE-/- mice. Interference with and detection of calcification was determined by a combination of quantitative calcium concentration measurements and fluorescence microscopy.
Results: In this setup, protein S Gla binding occurred already before any calcium salt deposits could be detected. Further, protein S Gla selectively binds to microcalcifications. Thus, protein S Gla interfers with both initiation and progression of hVSMC calcification in vitro. Equally, at low concentrations, protein S Gla-domain could be used to follow progression of calcification time-dependently without interfering with calcification process. Moreover, protein S-Gla was used to detect microcalcifications in atherosclerotic lesions ex vivo.
Conclusion(s): Protein S Gla-domain interferes and detects biological processes involved in VSMC driven calcium crystal formation and calcification progression.
To cite this abstract in AMA style:Gentier A, Agten S, Schurgers L, Hackeng T. Protein S Gla detects and attenuates early vascular calcification [abstract]. https://abstracts.isth.org/abstract/protein-s-gla-detects-and-attenuates-early-vascular-calcification/. Accessed September 27, 2023.
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