Aspirin‐triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein E−/− mice
Open accessAbstract
Background and Purpose: Atherosclerosis is characterized by a chronic non‐resolving inflammation in the arterial wall. Aspirin‐triggered lipoxin A4 (ATL) is a potent anti‐inflammatory mediator, involved in the resolution of inflammation. However, the therapeutic potential of immune targeting by means of ATL in atherosclerosis has not previously been explored. The aim of the present study was to determine the effects of ATL and its receptor Fpr2 on atherosclerosis development and progression in apolipoprotein E deficient (ApoE−/−) mice. Experimental Approach: ApoE−/− × Fpr2+/+ and ApoE−/− × Fpr2−/− mice were generated. Four‐week‐old mice fed a high‐fat diet for 4 weeks and 16‐week‐old mice fed chow diet received osmotic pumps containing either vehicle or ATL for 4 weeks. Atherosclerotic lesion size and cellular composition were measured in the aortic root and thoracic aorta. Lipid levels and leukocyte counts were measured in blood and mRNA was isolated from abdominal aorta and spleen. Key Results: ATL blocked atherosclerosis progression in the aortic root and thoracic aorta of ApoE−/− mice. In addition, ATL reduced macrophage infiltration and apoptotic cells in atherosclerotic lesions. The mRNA levels of several cytokines and chemokines in the spleen and aorta were reduced by ATL, whereas circulating leukocyte levels were unchanged. The ATL‐induced athero‐protection was absent in ApoE−/− mice lacking the Fpr2 receptor. Conclusion and Implications: ATL blocked atherosclerosis progression by means of an Fpr2‐mediated reduced local and systemic inflammation. These results suggest this anti‐inflammatory and pro‐resolving agent has therapeutic potential for the treatment of atherosclerosis. Linked Articles: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc
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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.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [99]
LXA4 administration with osmotic pumps to Apoe-knockout mice reduces atherosclerotic lesion size and inflammation, but does not alter the lesional phenotype of Apoe−/−Fpr2−/− mice.
“LXA4 administration with osmotic pumps to Apoe-knockout mice reduces atherosclerotic lesion size and inflammation, whereas this treatment does not alter the lesional phenotype of Apoe−/−Fpr2−/− mice99.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [99]
Treatment of Western-diet-fed Ldlr−/− mice with athero-targeted nanoparticles carrying an annexin A1-derived pro-resolving peptide Ac2-26 or with SPMs markedly suppressed formation of necrotic, thin-capped plaques.
“As summarized in this Review, treatment of Western-diet-fed Ldlr−/− mice with athero-targeted nanoparticles packaged with a pro-resolving peptide derived from annexin A1 (Ac2–26) or with SPMs markedly suppressed the formation of necrotic, thin-capped plaques36,38,99,109,118.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [99]
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- Authors
- Petri, M. H., Laguna‐Fernandez, A., Arnardottir, H., Wheelock, C. E., Perretti, M., Hansson, G. K., & Bäck, M.
- Affiliations
- Karolinska Institutet (SE)
- Experimental Cardiovascular Research Group, Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine Karolinska Institutet Stockholm Sweden
- Queen Mary University of London (GB)
- Karolinska University Hospital (SE)
- Corresponding author
- Bäck, Magnus
- ORCID
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2017-02-14
- Volume
- 174
- Issue
- 22
- Pages
- 4043-4054
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC5659998
- OpenAlex
- W2782423901
- Cited by
- 120
- References
- 37
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 10 · 2023: 9 · 2022: 23 · 2021: 16 · 2020: 11 · 2019: 9 · 2018: 11 · 2017: 10
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (086867/Z/08/Z)
- Stockholms Läns Landsting (20140222)
- Vetenskapsrådet (2014‐2312)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- atherosclerosis, ApoE-deficient mice, inflammation resolution, macrophage infiltration, atherosclerotic plaque, cytokines and chemokines, anti-inflammatory therapy, high-fat diet
- MeSH terms
- Animals, Aorta, Apolipoproteins E, Aspirin, Female, Cytokines, Mice, Knockout, Receptors, Formyl Peptide, Lipoxins, Atherosclerosis
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