Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 174, Issue 22, Pages 4043-4054Publisher
WILEY
DOI: 10.1111/bph.13707
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Funding
- Swedish Research Council [2014-2312]
- Swedish Heart and Lung Foundation [20150600, 20150683]
- Stockholm County Council [20140222]
- Wellcome Trust Programme [086867/Z/08/Z]
- KID PhD-fellowship from Karolinska Institutet
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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(-/-) x Fpr2(+/+) and ApoE(-/-) x 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.
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