Resolvin D1 Decreases Abdominal Aortic Aneurysm Formation by Lowering NETosis
Michael Spinosa, Gang Su, Morgan Salmon, Guanyi Lu, J. Michael Cullen, Anna Z. Fashandi, Robert B. Hawkins, Ashish K. Sharma, William Montgomery, Gorav Ailawadi, Gilbert R. Upchurch.
University of Virginia, Charlottesville, VA, USA.
Objectives: Resolvin treatment has been shown to attenuate abdominal aortic aneurysms in mice. NETosis, a process where neutrophils release neutrophil extracellular traps (NETs) to engulf and kill microbes, increases inflammation. The purpose of this study was to show a possible mechanism in which Resolvin D1 (RvD1) impacts abdominal aortic aneurysms through NETosis.
Methods: Abdominal aortic aneurysms (AAA) were induced in wild-type (WT) mice (C57BL/6; age 8-12 weeks) using topical (0.4 U/ml type 1 porcine pancreatic elastase) treatment or deactivated elastase as control. Mice were injected intravenously with 300ng RvD1 in 300Ál volume solution (or PBS as control) from day 0 to harvest on day 3 or day 14. The aortic diameters of mice harvested were measured using video micrometry and expressed as a percentage increase over an aorta control segment. Day 3 harvested mice had citrullinated H3 protein measured by western blot, MMP levels measured by gelatin zymography, and RvD1 serum levels measured by ELISA.
Results: Elastase-treated WT mice administered RvD1 demonstrated significantly decreased abdominal aortic diameter on day 14 compared to elastase-treated WT mice (84.9% vs. 136.5%, p=0.0003). Day 3 elastase-treated WT mice administered RvD1 and sham group showed decreased citrullinated H3, a NETosis marker, vs elastase-treated WT mice (p< 0.05). Gelatin zymography showed decreased levels of active MMP2 in the day 3 RvD1-treated group vs the elastase non-RvD1-treated group (p< 0.05). RvD1 serum levels were significantly higher in the day 3 elastase WT group vs sham group (p< 0.05).
Conclusion: RvD1-treated mice showed lower levels of NETosis and modulate inflammation early in murine AAA formation, which provides a possible mechanism for how resolvins attenuate AAA in mice. Future cytokine analysis and Immunohistochemistry is planned to further investigate the mechanism.
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