2. Academic Validation
  3. Proteomics reveals spatial and molecular heterogeneities in advanced atherosclerotic carotid artery plaques

Proteomics reveals spatial and molecular heterogeneities in advanced atherosclerotic carotid artery plaques

  • Nat Cardiovasc Res. 2026 Jun 22. doi: 10.1038/s44161-026-00827-1.
Ankit Sinha # 1 2,  Nadja Sachs # 2 3,  Elena Kratz 1,  Jessica Pauli 2 4,  Sophia Steigerwald 1,  Vincent Albrecht 1,  Thierry M Nordmann 1 5 6 7,  Enes Ugur 1,  Edwin H Rodriguez 1,  Marie-Luise Engl 3,  Patricia Skowronek 1,  Denys Oliinyk 1,  Andreas Metousis 1,  Moritz von Scheidt 2 8,  Michael Wierer 1 9,  Hanna Winter 2 4,  Heribert Schunkert 2 8,  Daniela Branzan 3,  Lars Maegdefessel # 10 11 12,  Matthias Mann # 13 14
Affiliations

Affiliations

  • 1 Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 2 German Centre for Cardiovascular Research (DZHK) Partner site Munich Heart Alliance, Munich, Germany.
  • 3 Department for Vascular and Endovascular Surgery, TUM Klinikum, Technical University Munich, Munich, Germany.
  • 4 Institute of Molecular Vascular Medicine, TUM Klinikum, TUM, Munich, Germany.
  • 5 Molecular and Spatial Biology of Skin, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 6 Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany.
  • 7 Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
  • 8 Department of Cardiology, Deutsches Herzzentrum, TUM Klinikum, Munich, Germany.
  • 9 Proteomics Research Infrastructure, University of Copenhagen, Copenhagen, Denmark.
  • 10 German Centre for Cardiovascular Research (DZHK) Partner site Munich Heart Alliance, Munich, Germany. [email protected].
  • 11 Institute of Molecular Vascular Medicine, TUM Klinikum, TUM, Munich, Germany. [email protected].
  • 12 Department of Medicine, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. [email protected].
  • 13 Max Planck Institute of Biochemistry, Martinsried, Germany. [email protected].
  • 14 German Centre for Cardiovascular Research (DZHK) Partner site Munich Heart Alliance, Munich, Germany. [email protected].
  • # Contributed equally.
PMID: 42332205 DOI: 10.1038/s44161-026-00827-1
Abstract

Atherosclerotic plaque rupture is a major cause of cerebrovascular events, yet the molecular determinants underlying vulnerability-related plaque morphology, including fibrous-cap thickness, remain incompletely defined. Using histomorphology-guided spatial proteomics, here we delineate molecular programs associated with plaque cap phenotype across discrete plaque subregions. In 112 carotid endarterectomy specimens, differences between thin-cap and thick-cap plaques were predominantly localized to the necrotic core and fibrous cap. These differences were enriched for processes related to inflammation, lipid handling, extracellular matrix remodeling and ossification/calcification, and supported the presence of proteome-based plaque subtypes. PCSK9 was among the proteins most strongly associated with thin-cap plaques. Consistently, an in vitro model of necrotic core-like oxidative and inflammatory stress increased PCSK9 secretion in primary vascular smooth muscle cells. Together, these findings localize molecular programs associated with cap phenotype to plaque compartments and provide a framework for spatially informed biomarker discovery in advanced carotid atherosclerosis.

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