Legumain is upregulated in acute cardiovascular events and associated with improved outcome - potentially related to anti-inflammatory effects on macrophages

Research output: Contribution to journalArticle

Abstract

Background and aims: We have previously found increased levels of the cysteine protease legumain in plasma and plaques from patients with carotid atherosclerosis. This study further investigated legumain during acute cardiovascular events. Methods: Circulating levels of legumain from patients and legumain released from platelets were assessed by enzyme-linked-immunosorbent assay. Quantitative PCR and immunoblotting were used to study expression, while localization was visualized by immunohistochemistry. Results: In the SUMMIT Malmö cohort (n = 339 with or without type 2 diabetes and/or cardiovascular disease [CVD], and 64 healthy controls), the levels of circulating legumain were associated with the presence of CVD in non-diabetics, with no relation to outcome. In symptomatic carotid plaques and in samples from both coronary and intracerebral thrombi obtained during acute cardiovascular events, legumain was co-localized with macrophages in the same regions as platelets. In vitro, legumain was shown to be present in and released from platelets upon activation. In addition, THP-1 macrophages exposed to releasate from activated platelets showed increased legumain expression. Interestingly, primary peripheral blood mononuclear cells stimulated with recombinant legumain promoted anti-inflammatory responses. Finally, in a STEMI population (POSTEMI; n = 272), patients had significantly higher circulating legumain before and immediately after percutaneous coronary intervention compared with healthy controls (n = 67), and high levels were associated with improved outcome. Conclusions: Our data demonstrate for the first time that legumain is upregulated during acute cardiovascular events and is associated with improved outcome.

Details

Authors
  • Ngoc Nguyen Lunde
  • Ida Gregersen
  • Thor Ueland
  • Christian Shetelig
  • Sverre Holm
  • Xiang Yi Kong
  • Annika E. Michelsen
  • Kari Otterdal
  • Arne Yndestad
  • Kaspar Broch
  • Lars Gullestad
  • Tuula A. Nyman
  • Bjørn Bendz
  • Jan Eritsland
  • Pavel Hoffmann
  • Karolina Skagen
  • Magnus Grenegård
  • Marcin Poreba
  • Marcin Drag
  • Ingebjørg Seljeflot
  • Bjørnar Sporsheim
  • Terje Espevik
  • Mona Skjelland
  • Harald Thidemann Johansen
  • Rigmor Solberg
  • Pål Aukrust
  • Geir Øystein Andersen
  • Bente Halvorsen
Organisations
External organisations
  • University of Oslo
  • UiT The Arctic University of Norway, Tromsø
  • Oslo university hospital
  • Norwegian Radium Hospital
  • Skåne University Hospital
  • Örebro University
  • Wrocław University of Science and Technology
  • Norwegian University of Science and Technology
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems

Keywords

  • Cardiovascular disease, Legumain, Macrophage, Plaque modification, Platelets, Protease
Original languageEnglish
JournalAtherosclerosis
Publication statusE-pub ahead of print - 2019 Dec 14
Publication categoryResearch
Peer-reviewedYes