D-series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization.
The role of resolvins in abdominal aortic aneurysm (AAA) has not been established. We hypothesized that treatment with D-series resolvins (RvD2 or RvD1) would attenuate murine AAA formation through alterations in macrophage polarization and cytokine expression. Male C57/B6 mice (n = 9 per group) 8 to 12 wk old received RvD2 (100 ng/kg/treatment), RvD1 (100 ng/kg/treatment), or vehicle only every third day beginning 3 d before abdominal aortic perfusion with elastase as prevention. Aortas were collected 14 d after elastase perfusion. Cytokine analysis (n = 5 per group) or confocal microscopy (n = 4 per group) was performed. In a separate experiment, RvD2 was provided to mice with small AAAs 3 d after elastase treatment (n = 8 per group). Additionally, apolipoprotein E knockout mice treated with angiotensin II (1000 ng/kg) were treated with RvD2 or vehicle alone (n = 10 per group) in a nonsurgical model of AAA. To determine the effect of RvD2 on macrophage polarization, confocal staining for macrophages, M1 and M2 macrophage subtypes, α-actin, and DAPI was performed. Mean aortic dilation was 96 ± 13% for vehicle-treated mice, 57 ± 9.7% for RvD2-treated mice, and 61 ± 11% for RvD1-treated mice (P < 0.0001). Proinflammatory cytokines macrophage chemotactic protein 1, C-X-C motif ligand 1, and IL-1β were significantly elevated in control animals compared to RvD2- and RvD1-treated animals (P < 0.05), resulting in a reduction of matrix metalloproteinase 2 and 9 activity in resolvin-treated mice in both elastase and angiotensin II models. Treatment of existing small AAAs with RvD2 demonstrated a 25% reduction in aneurysm size at d 14 compared to vehicle alone (P = 0.018). Confocal histology demonstrated a prevalence of M2 macrophages within the aortic medium in mice treated with RvD2. Resolvin D2 exhibits a potent protective effect against experimental AAA formation. Treatment with RvD2 significantly influences macrophage polarization and decreases several important proinflammatory cytokines. Resolvins and the alteration of macrophage polarization represent potential future targets for prevention of AAA.-Pope, N. H., Salmon, M., Davis, J. P., Chatterjee, A., Su, G., Conte, M. S., Ailawadi, G., Upchurch, G. R., Jr. D-series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization.
Department of Surgery, University of Virginia, Charlottesville, Virginia, USA; and.
Nicolas H
NH
Pope
Department of Surgery, University of Virginia, Charlottesville, Virginia, USA; and.
Morgan
M
Salmon
Department of Surgery, University of Virginia, Charlottesville, Virginia, USA; and.
John P
JP
Davis
Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, California, USA.
Anuran
A
Chatterjee
Department of Surgery, University of Virginia, Charlottesville, Virginia, USA; and.
Gang
G
Su
Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, California, USA.
Michael S
MS
Conte
Department of Surgery, University of Virginia, Charlottesville, Virginia, USA; and.
Gorav
G
Ailawadi
Department of Surgery, University of Virginia, Charlottesville, Virginia, USA; and np7g@virginia.edu.
Gilbert R
GR
Upchurch
D000199:Actins / Q000378:metabolism; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism* / Q000517:prevention & control; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D000199:Actins; D016207:Cytokines; D053583:Interleukin-1beta; C545423:resolvin D2; D004281:Docosahexaenoic Acids; D020778:Matrix Metalloproteinase 2
inflammation; proresolving mediators; vascular biology