D‐series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization

Abstract

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.

A cluster of immunoresolvents links coagulation to innate host defense in human blood

“…S2), it was not apparently increased in abundance during coagulation. RvD2 is produced by human adipocytes (14) and other human tissues (15–17), prevents secondary thrombosis and necrosis in dermal burn wounds (18), and is protective in abdominal aortic aneurysm (19). Principal component analysis (PCA) confirmed that the production of TXB 2 , PGD 2 , and LTB 4 were associated with early time points, whereas the specific SPM cluster was associated with later times during coagulation (Fig.…”

“…Thus, clearing of adenosine increased platelet-neutrophil aggregation and the biosynthesis of RvD3, RvD4, and RvD6, which enabled quantitation of the full spectrum of D-series resolvins, except for RvD2, which was not increased during whole-blood coagulation (Fig. 1), yet is protective against abdominal aortic aneurysm (19) and secondary thrombosis and necrosis in thermal burn wounds (18). SPMs also stimulate macrophages to phagocytize thrombi in the form of fibrin clots (53), which may facilitate the remodeling of clots or their removal.…”

Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications

“…Treatment with n-3 PUFA has previously been implicated as a potential therapeutic strategy in this context (Wales, Kavazos et al 2014). Pope and colleagues demonstrated that systemic administration of either RvD1 or RvD2 (100 ng/kg IP every 3 days) significantly decreased AAA formation in a surgical elastase-perfusion model, associated with preservation of elastin, reduced macrophage (but not T-cell) infiltration, a broad reduction in local inflammatory cytokine signals (TNF-α, IL-1α, IL-1β, MCP-1, CXCL-1, RANTES), increase anti-inflammatory cytokines (IL-10), and reduction in MMP activity by gelatin zymography (Pope, Salmon et al 2016). When specifically examined, RvD2 treatment resulted in a shift in aortic wall macrophage phenotype favoring M2 polarization.…”

Mesenchymal stem cell–derived conditioned medium attenuate angiotensin II‐induced aortic aneurysm growth by modulating macrophage polarization

“…The rapamycin inhibitor everolimus limited angiotensin II (AngII)‐induced AA formation in apolipoprotein E‐deficient (apoE −/− ) mice via suppressed development of bone marrow CCR2 monocytes and diminished M1 polarization . D‐series resolvins could attenuate inflammatory activities and AA formation by increasing M2 macrophage polarization . Elastin‐derived peptides (EDPs) promoted a pro‐inflammatory environment in aortic tissues and attenuated aortic dilation through induction of M1 polarization, and neutralization of EDPs.…”