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

Abstract

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 (PPARγ). Moreover, the protective effect of NO₂-OA relies on the inhibition of macrophage prostaglandin E2 (PGE₂)-induced PGE₂ 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.

Keywords: Abdominal aortic aneurysm; Aortic disease; Macrophage; Nitro-fatty acid.