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

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.

• 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, Isabel Gonçalves, Jan Nilsson, Magnus Grenegård, Marcin Poreba, Marcin Drag, Ingebjørg Seljeflot, Bjørnar Sporsheim, Terje Espevik, Mona Skjelland, Harald Thidemann Johansen, Rigmor Solberg, Pål Aukrust, Harry Björkbacka, Geir Øystein Andersen, Bente Halvorsen
• Journal: Atherosclerosis (Atherosclerosis) Vol. 296 Pg. 74-82 (03 2020) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 31870625 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• Lipopolysaccharides
• Recombinant Proteins
• Cysteine Endopeptidases
• asparaginylendopeptidase

Topics

• Acute Disease
• Amino Acid Sequence
• Blood Platelets (metabolism)
• Cardiovascular Diseases (complications, metabolism, pathology)
• Carotid Artery Diseases (metabolism, pathology)
• Cross-Sectional Studies
• Cysteine Endopeptidases (biosynthesis, blood, genetics, pharmacology)
• Cytokines (pharmacology)
• Diabetes Mellitus, Type 2 (blood, complications)
• Follow-Up Studies
• Humans
• Lipopolysaccharides (pharmacology)
• Macrophages (enzymology)
• Monocytes (drug effects)
• Percutaneous Coronary Intervention
• Plaque, Atherosclerotic (chemistry)
• Platelet Activation
• Recombinant Proteins (pharmacology)
• ST Elevation Myocardial Infarction (blood, mortality, surgery)
• Sweden (epidemiology)
• THP-1 Cells