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Carotid plaque rupture is a major cause of cerebrovascular events, yet predicting which plaques will rupture remains challenging. While severe stenosis was once the primary indicator for stroke risk, recent evidence shows that plaques with moderate stenosis can also rupture, highlighting the importance of understanding plaque composition at the molecular level.

Sinha et al. aimed to identify distinct protein signatures associated with carotid plaque vulnerability by examining the spatial heterogeneity of plaques. For serum proteomes, peptides were separated on an Aurora Elite CSI 15×75 C18 UHPLC column using the 60SPD method on an Evosep One system, coupled to an Orbitrap Astral via an EASY-Spray source. For vascular smooth muscle cell proteomes, peptides were separated on an Aurora Elite column using the 40SPD method on an Evosep One system, coupled to a timsTOF Ultra.

This quantitative proteomics approach identified 4,893 unique proteins across all subregions. The researchers developed a seven-protein panel from the necrotic core and fibrous cap that predicted plaque vulnerability with high accuracy (AUC = 0.86). They also created a 12-protein serum signature with an AUC of 0.67.

The study revealed that the necrotic core exhibits the most distinctive vulnerability-associated proteome, with upregulation of proteins involved in inflammation, lipid metabolism, and matrix remodelling. The researchers demonstrated that vascular smooth muscle cells under inflammatory stress produce PCSK9, contributing to plaque vulnerability.

This research advances our understanding of the molecular mechanisms underlying plaque vulnerability and offers potential biomarkers for risk stratification, which could lead to more targeted interventions and improved prevention of cerebrovascular events.

Publication
medRxiv

Authors

Ankit Sinha, Nadja Sachs, Elena Kratz, Jessica Pauli, Sophia Steigerwald, Vincent Albrecht, Thierry Nordmann, Enes Ugur, Edwin H Rodriguez, Marie-Luise Engl, Patricia Skowronek, Moritz von Scheidt, Hanna Winter, Daniela Branzan, Heribert Schunkert, Lars Maegdefessel, Matthias Mann

Title

Spatially resolved proteomic signatures of atherosclerotic carotid artery disease