Suppression of Vascular Macrophage Activation by Nitro-Oleic Acid and its Implication for Abdominal Aortic Aneurysm Therapy

Purpose Abdominal aortic aneurysm (AAA) is one of the leading causes of death in the developed world and is currently undertreated due to the complicated nature of the disease. Herein, we aimed to address the therapeutic potential of a novel class of pleiotropic mediators, specifically a new drug candidate, nitro-oleic acid (NO2-OA), on AAA, in a well-characterized murine AAA model. Methods We generated AAA using a mouse model combining AAV.PCSK9-D377Y induced hypercholesterolemia with angiotensin II given by chronic infusion. Vehicle control (PEG-400), oleic acid (OA), or NO2-OA were subcutaneously delivered to mice using an osmotic minipump. We characterized the effects of NO2-OA on pathophysiological responses and dissected the underlying molecular mechanisms through various in vitro and ex vivo strategies. Results Subcutaneous administration of NO2-OA significantly decreased the AAA incidence (8/28 mice) and supra-renal aorta diameters compared to mice infused with either PEG-400 (13/19,p = 0.0117) or OA (16/23,p = 0.0078). In parallel, the infusion of NO2-OA in the AAA model drastically decreased extracellular matrix degradation, inflammatory cytokine levels, and leucocyte/macrophage infiltration in the vasculature. Administration of NO2-OA reduced inflammation, cytokine secretion, and cell migration triggered by various biological stimuli in primary and macrophage cell lines partially through activation of the peroxisome proliferator-activated receptor-gamma (PPAR gamma). Moreover, the protective effect of NO2-OA relies on the inhibition of macrophage prostaglandin E2 (PGE(2))-induced PGE(2)receptor 4 (EP4) cAMP signaling, known to participate in the development of AAA. Conclusion Administration of NO2-OA protects against AAA formation and multifactorial macrophage activation. With NO2-OA currently undergoing FDA approved phase II clinical trials, these findings may expedite the use of this nitro-fatty acid for AAA therapy.

Automated summary

Administration of NO2-OA significantly reduces the incidence of AAA and the diameter of the supra-renal aorta in a mouse model. It also decreases extracellular matrix degradation, inflammatory cytokine levels, and leucocyte/macrophage infiltration in the vasculature. The protective effect of NO2-OA is partially mediated through activation of PPAR gamma and inhibition of macrophage prostaglandin E2-induced EP4 cAMP signaling.