Author + information
- Received April 2, 2018
- Revision received August 13, 2018
- Accepted August 14, 2018
- Published online September 14, 2018.
- Marcelo H. Petri, MD PhDa,
- Silke Thul, PhDa,
- Teodora Andonova, MScia,
- Moritz Lindquist-Liljeqvist, MDb,
- Hong Jin, MD PhDa,
- Nikolaos-Taxiarchis Skenteris, MScia,
- 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,∗ ()
- aDepartment of Medicine, Karolinska Institutet, Stockholm, 171 77, Sweden
- bDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, 171 77, Sweden
- cDepartment of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- dWilliam Harvey Research Institute, Barts and The 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, 171 77, Sweden
- ↵∗Address for correspondence: Magnus Bäck Translational Cardiology Center for Molecular Medicine L8:03 Karolinska University Hospital 171 76 Stockholm, Sweden Tel: +46-8-51770000 Fax: +46-8-313147.
• Specialized lipid mediators transduce the resolution of inflammation by means of the receptor ALX/FPR2.
• Human abdominal aortic aneurysm (AAA) exhibited decreased ALX/FPR2 expression.
• Genetic disruption of the murine ALX/FPR2 orthologue exacerbated AAA and increased inflammation.
• The ALX/FPR2 agonist aspirin-triggered lipoxin (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.
AAA is a progressive aortic dilatation that may lead to rupture, which is usually lethal. Here, we identify a state of failure in the resolution of inflammation by means of decreased expression of the pro-resolving receptor ALX/FPR2 in the adventitia of human AAA lesions. Mimicking this condition by genetic deletion of the murine ALX/FPR2 orthologue in hyperlipidemic mice exacerbated the aortic dilatation induced by angiotensin-II infusion, associated with decreased vascular collagen and increased inflammation. Key roles of lipoxin formation through 12/15-lipoxygenase and neutrophil p38 mitogen-activated protein kinase we also established. In conclusion, we establish that pro-resolving signaling by means of the ALX/FPR2 receptor in aneurysms and vascular inflammation.
Conflicts of interest: None
Funding: This work was supported by supported by grants from the Swedish Research Council (2014-2312), Swedish Heart and Lung Foundation (20150600 and 20150683), Marianne and Marcus Wallenberg Foundation (2015.0104), King Gustaf V’s and Queen Victoria’s Freemason Foundation, and the Stockholm County Council (20150869 and 20170365). Marcelo H Petri was supported by a KID PhD-fellowship from Karolinska Institutet. Silke Thul was supported by the Deutsche Forschungsgemeinschaft (DFG) through a research fellowship (MU 3851/1-1). Kenneth Caidahl was supported by the Swedish Research Council (Grant number 2011-3579); the Swedish Heart and Lung Foundation (grant number 20150423); and the Stockholm County Council (grant number 20150517). Mauro Perretti was supported by the Wellcome Trust Programme (grant number 086867/Z/08/Z). Joy Roy was supported by the Stockholm County Council (grant numbers 20150906 and SLL-HMT:20160861).
- Received April 2, 2018.
- Revision received August 13, 2018.
- Accepted August 14, 2018.