Cited by 127Atherosclerosis and Cardiovascular DiseasesCerebrovascular and Carotid Artery DiseasesCholesterol and Lipid Metabolism

The role of the FPR2/ALX receptor in atherosclerosis development and plaque stability

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Petri, Marcelo H., Laguna-Fernández, Andrés, Gonzalez-Diez, Maria, Paulsson-Berne, Gabrielle, Hansson, Göran K., Bäck, Magnus·2015·Cardiovascular Research

Abstract

AIMS: The formyl peptide receptor (FPR) subtype FPR2/ALX transduces pro-inflammatory responses and participates in the resolution of inflammation depending on activation. The aim of the present study was to unravel the role of FPR2/ALX signalling in atherosclerosis. METHODS AND RESULTS: Expression of FPR2/ALX was analysed in 127 human carotid atherosclerotic lesions and revealed that this receptor was expressed on macrophages, smooth muscle cells (SMCs), and endothelial cells. Furthermore, FPR2/ALX mRNA levels were significantly up-regulated in atherosclerotic lesions compared with healthy vessels. In multiple regression, age, creatinine, and clinical signs of increased cerebral ischaemia were independent predictors of FPR2/ALX expression. To provide mechanistic insights into these observations, we generated Ldlr(-/-)xFpr2(-/-) mice, which exhibited delayed atherosclerosis development and less macrophage infiltration compared with Ldlr(-/-)xFpr2(+/+) mice. These findings were reproduced by transplantation of Fpr2(-/-) bone marrow into Ldlr(-/-) mice and further extended by in vitro experiments, demonstrating a lower inflammatory state in Fpr2(-/-) macrophages. FPR2/ALX expression correlated with chemo- and cytokines in human atherosclerotic lesions and leucocytes. Finally, atherosclerotic lesions in Ldlr(-/-)xFpr2(-/-) mice exhibited decreased collagen content, and Fpr2(-/-) SMCs exhibited a profile of increased collagenase and decreased collagen production pathways. CONCLUSION: FPR2/ALX is proatherogenic due to effects on bone marrow-derived cells, but promoted a more stable plaque phenotype through effects on SMCs. Taken together, these results suggest a dual role of FPR2/ALX signalling in atherosclerosis by way of promoting disease progression and but increasing plaque stability.

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  • ALX/FPR2 and ChemR23 are expressed in human aortic, coronary, and carotid atherosclerotic lesions, indicating that their pro-resolving ligands act locally within the vascular wall.

    “These receptors are expressed in human aortic, coronary and carotid atherosclerotic lesions104–106, indicating that their pro-resolving ligands exert local effects within the vascular wall (TABLE 1).”
  • Genetic targeting of the murine ALX/FPR2 homologue in hyperlipidaemic mice showed that ALX/FPR2 deficiency reduced atherosclerosis consistently in different mouse models.

    “A study on genetic targeting of the murine ALX/FPR2 homologue in hyperlipidaemic mice provided arguments in favour of this hypothesis by showing that ALX/FPR2 deficiency reduced atherosclerosis consistently in different mouse models99,104.”

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Authors
Petri, M. H., Laguna-Fernández, A., Gonzalez-Diez, M., Paulsson-Berne, G., Hansson, G. K., & Bäck, M.
Affiliations
Karolinska University Hospital (SE)
Corresponding author
Bäck, Magnus
Venue
Cardiovascular Research
Published
2014-10-23
Volume
105
Issue
1
Pages
65-74
ISSN
  • 0008-6363 (ISSN-L)
  • 1755-3245
OpenAlex
W2000987582
Cited by
125
References
44
Citations by year
2026: 3 · 2025: 11 · 2024: 9 · 2023: 13 · 2022: 20 · 2021: 14 · 2020: 7 · 2019: 10 · 2018: 13 · 2017: 10 · 2016: 7 · 2015: 6 · 2014: 2
FWCI
3.81
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Cardiovascular Research (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Stockholms Läns Landsting (20120297)
  • Vetenskapsrådet (2011-02988, 20120827, 2012-02577, 20120474)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
FPR2/ALX, formyl peptide receptor, atherosclerosis, plaque stability, macrophage infiltration, smooth muscle cells, collagen synthesis, collagenase, inflammation, bone marrow-derived cells, Ldlr knockout mice, cerebral ischemia
MeSH terms
Aged, Aged, 80 and over, Animals, Carotid Artery Diseases, Collagen, Female, Humans, Macrophages, Male, Middle Aged, Receptors, LDL, RNA, Messenger, Signal Transduction, Up-Regulation, Bone Marrow Transplantation, Carotid Stenosis, Mice, Knockout, Myocytes, Smooth Muscle, Receptors, Formyl Peptide, Receptors, Lipoxin, Atherosclerosis, Mice, Plaque, Atherosclerotic

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