November 2024 - Stefan Stojković

Priv.-Doz. Dr. Stefan Stojković, PhD

MedUni Wien RESEARCHER OF THE MONTH November 2024

Using proteomics, we aimed to reveal molecular types of human atherosclerotic lesions and study their associations with histology, imaging and cardiovascular outcomes. In the largest proteomic study up to date, 219 carotid endarterectomy samples were procured from 120 patients. This extensive proteomics analysis identified plaque inflammation and calcification signatures, which were inversely correlated and validated using targeted proteomics. The inflammation signature was characterized by the presence of neutrophil-derived proteins, such as S100A8/9 and myeloperoxidase, while the calcification signature included fetuin-A, osteopontin, and gamma-carboxylated proteins. The proteomics data also revealed sex differences in atherosclerosis, with large-aggregating proteoglycans versican and aggrecan being more abundant in females and exhibiting an inverse correlation with estradiol levels. The integration of RNA sequencing data attributed the inflammation signature predominantly to neutrophils and macrophages, and the calcification and sex signatures to smooth muscle cells, except for certain plasma proteins that were not expressed but retained in plaques, such as fetuin-A. A protein signature of 4 key proteins (calponin, protein C, serpin H1, and versican) predicted future cardiovascular mortality in the discovery and validation cohort, respectively, surpassing the prognostic performance of imaging and histology. Plaque proteomics redefined clinically relevant patient groups with distinct outcomes, in particular postmenopausal women with higher accumulation of large-aggregating proteoglycans had an elevated risk of future cardiovascular events.

Selected Literature

1. Theofilatos K*, Stojkovic S*, Hasman M, van der Laan SW, Baig F, Barallobre-Barreiro J, Schmidt LE, Yin S, Yin X, Burnap S, Singh B, Popham J, Harkot O, Kampf S, Nackenhorst MC, Strassl A, Loewe C, Demyanets S, Neumayer C, Bilban M, Hengstenberg C, Huber K, Pasterkamp G, Wojta J, Mayr M. - Proteomic Atlas of Atherosclerosis: The Contribution of Proteoglycans to Sex Differences, Plaque Phenotypes, and Outcomes. Circ Res. 2023 Sep 15;133(7):542-558. doi: 10.1161/CIRCRESAHA.123.322590. Epub 2023 Aug 30.
2. Stojkovic S, Kaun C, Heinz M, Krychtiuk KA, Rauscher S, Lemberger CE, de Martin R, Gröger M, Petzelbauer P, Huk I, Huber K, Wojta J, Demyanets S. - Interleukin-33 induces urokinase in human endothelial cells - possible impact on angiogenesis. Journal of        Thrombosis and Haemostasis. 2014 Jun;12(6):948-57. doi:10.1111/jth.12581.
3. Stojkovic S, Kampf  S, Harkot O, Nackenhorst M, Brekalo M, Huber K, Hengstenberg C, Neumayer C, Wojta J, Demyanets S. - Soluble ST2 in Patients with Carotid Artery Stenosis-Association with Plaque Morphology and Long-Term Outcome. Int J Mol Sci. 2023 May 19;24(10):9007. doi: 10.3390/ijms24109007.
4. Stojkovic S, Demyanets S, Kopp CW, Hengstenberg C, Wojta J, Eichelberger B, Panzer S, Gremmel T. - Association of soluble suppression of tumorigenesis 2 (sST2) with platelet activation, monocyte tissue factor and ischemic outcomes following angioplasty and stenting. Front. Cardiovasc. Med. 2020| doi: 10.3389/fcvm.2020.605669.
5. Stojkovic S, Thulin A, Hell L, Rauscher S, Baumgartner J, Gröger M, Ay C, Wojta J,  Siegbahn A, Åberg M. - Effects of interleukin-33 on tissue factor expression in human monocyte subsets. Thrombosis and Haemostasis. 2017 Jun 28;117(7):1379-1390. doi: 10.1160/TH1610-0784. Epub 2017 May 11.
6. Stojkovic S, Kaun C, Basilio J, Rauscher S, Hell L, Krychtiuk KA, Bonstingl C, de Martin R, Gröger M, Ay C, Holnthoner W, Eppel W, Neumayer C, Huk I, Huber K, Demyanets S, Wojta J. - Tissue factor is induced by interleukin-33 in human endothelial cells: a new link between coagulation and inflammation. Scientific reports 2016 May 4;6:25171. doi: 10.1038/srep25171.
7. Stojkovic S, Wadowski P, Haider P, Weikert C, Pultar J, Lee S, Eichelberger B, Hengstenberg C, Wojta J, Panzer S, Demyanets S, Gremmel T. - Circulating microRNAs and monocyte-platelet aggregate formation in acute coronary syndrome. Thromb Haemost. 2021 Jan 14. doi: 10.1055/s-0040-1722226. Online ahead of print.
8. Stojkovic S*, Koller L*, Sulzgruber P, Hülsman M, Huber K, Mayr M, Hengstenberg C, Wojta J, Niessner A. - Liver-specific microRNA-122 as prognostic biomarker in patients with chronic systolic heart failure. Int J Cardiol. 2019 Nov 7. pii: S0167-5273(19)33664-2. doi: 10.1016/j.ijcard.2019.11.090.
9. Stojkovic S, Jurisic M, Kopp CW, Koppensteiner R, Huber K, Wojta J, Gremmel T. - Circulating micro RNAs identify patients at increased risk of in-stent restenosis after peripheral angioplasty with stent implantation. Atherosclerosis, 2018 Feb;269:197-203. doi: 10.1016/j.atherosclerosis.2018.01.020. Epub 2018 Jan 16.
10. Stojkovic S, Kaider A, Koller L, Maurer G, Wojta J, Schmidinger H, Diedrich A, Demyanets S, Pezawas T. - GDF-15 versus soluble ST2 for risk stratification of arrhythmic death in non-ischemic, dilated cardiomyopathy. Journal of Cellular and Molecular Medicine, 2018 Apr;22(4):2422-2429. doi: 10.1111/jcmm.13540. Epub 2018 Feb 4.