Resolution of Inflammation Through the Lipoxin and ALX/FPR2 Receptor Pathway Protects Against Abdominal Aortic Aneurysms
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- Received April 2, 2018
- Revision received August 13, 2018
- Accepted August 14, 2018
- Published online December 31, 2018.
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Author Information
- Marcelo H. Petri, MD, PhDa,
- Silke Thul, PhDa,
- Teodora Andonova, MSca,
- Moritz Lindquist-Liljeqvist, MDb,
- Hong Jin, MD, PhDa,
- Nikolaos-Taxiarchis Skenteris, MSca,
- Hildur Arnardottir, PhDa,
- Lars Maegdefessel, MD, PhDa,
- Kenneth Caidahl, MD, PhDb,c,
- Mauro Perretti, PhDd,
- Joy Roy, MD, PhDb,e and
- Magnus Bäck, MD, PhDa,e,∗ (Magnus.Back{at}ki.se)
- aDepartment of Medicine, Karolinska Institutet, Stockholm, Sweden
- bDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- cDepartment of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- dWilliam Harvey Research Institute, Barts and London School of Medicine, Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, United Kingdom
- eTheme Heart and Vessels, Division of Valvular and Coronary Disease, Karolinska University Hospital, Stockholm, Sweden
- ↵∗Address for correspondence:
Dr. Magnus Bäck, Translational Cardiology, S1:02, Karolinska University Hospital, 171 76 Stockholm, Sweden.
Visual Abstract
Highlights
• Specialized lipid mediators transduce the resolution of inflammation by means of the ALX/FPR2.
• Human AAA exhibited decreased ALX/FPR2 expression.
• Genetic disruption of the murine ALX/FPR2 ortholog exacerbated AAA and increased inflammation.
• The ALX/FPR2 agonist ATL induced pro-resolving signaling in bone marrow-derived murine cells.
• Pro-resolving signaling by means of the ALX/FPR2 receptor may decrease the progression of AAA.
Summary
An abdominal aortic aneurysm (AAA) is a progressive aortic dilation that may lead to rupture, which is usually lethal. This study identifies the state of failure in the resolution of inflammation by means of decreased expression of the pro-resolving receptor A lipoxin/formyl peptide receptor 2 (ALX/FPR2) in the adventitia of human AAA lesions. Mimicking this condition by genetic deletion of the murine ALX/FPR2 ortholog in hyperlipidemic mice exacerbated the aortic dilation induced by angiotensin II infusion, associated with decreased vascular collagen and increased inflammation. The authors also identified key roles of lipoxin formation through 12/15-lipoxygenase and neutrophil p38 mitogen-activated protein kinase. In conclusion, this study established pro-resolving signaling by means of the ALX/FPR2 receptor in aneurysms and vascular inflammation.
Footnotes
Supported by Swedish Research Council grant 2014-2312, Swedish Heart and Lung Foundation grants 20150600 and 20150683, Marianne and Marcus Wallenberg Foundation grant 2015.0104, King Gustaf V’s and Queen Victoria’s Freemason Foundation, and Stockholm County Council grants 20150869 and 20170365. Dr. Petri was supported by a KID PhD fellowship from Karolinska Institutet. Dr. Thul was supported by the Deutsche Forschungsgemeinschaft through research fellowship award MU 3851/1-1. Dr. Caidahl was supported by Swedish Research Council grant 2011-3579, Swedish Heart and Lung Foundation grant 20150423, and Stockholm County Council grant 20150517. Dr. Perretti was supported by Wellcome Trust grant 086867/Z/08/Z. Dr. Roy was supported by Stockholm County Council grants 20150906 and SLL-HMT:20160861. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received April 2, 2018.
- Revision received August 13, 2018.
- Accepted August 14, 2018.
- 2018 The Authors
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- Supplemental Tables 1 and 2 and Supplemental Material[S2452302X18302249_mmc1.pdf]