Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
Cardiovasc Drugs Ther. 2021 Oct;35(5):939-951. doi: 10.1007/s10557-020-07031-8. Epub 2020 Jul 15.
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 (NO-OA), on AAA, in a well-characterized murine AAA model.
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 NO-OA were subcutaneously delivered to mice using an osmotic minipump. We characterized the effects of NO-OA on pathophysiological responses and dissected the underlying molecular mechanisms through various in vitro and ex vivo strategies.
Subcutaneous administration of NO-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 NO-OA in the AAA model drastically decreased extracellular matrix degradation, inflammatory cytokine levels, and leucocyte/macrophage infiltration in the vasculature. Administration of NO-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 NO-OA relies on the inhibition of macrophage prostaglandin E2 (PGE)-induced PGE receptor 4 (EP4) cAMP signaling, known to participate in the development of AAA.
Administration of NO-OA protects against AAA formation and multifactorial macrophage activation. With NO-OA currently undergoing FDA approved phase II clinical trials, these findings may expedite the use of this nitro-fatty acid for AAA therapy.
腹主动脉瘤（AAA）是发达国家主要的死亡原因之一，由于疾病的复杂性，目前治疗不足。在此，我们旨在探讨一类新型的多功能介质——新型药物候选物硝基油酸（NO-OA）在一种经过充分验证的小鼠 AAA 模型中的治疗潜力。
我们通过一种结合 AAV.PCSK9-D377Y 诱导的高胆固醇血症和血管紧张素 II 慢性输注的小鼠模型生成 AAA。通过渗透型迷你泵，以皮下注射方式向小鼠给予载体对照（PEG-400）、油酸（OA）或 NO-OA。我们通过各种体外和离体策略来表征 NO-OA 对病理生理反应的影响，并剖析其潜在的分子机制。
与给予 PEG-400（13/19，p=0.0117）或 OA（16/23，p=0.0078）的小鼠相比，NO-OA 的皮下给药显著降低了 AAA 的发生率（8/28 只小鼠）和肾上主动脉直径。同时，NO-OA 在 AAA 模型中的输注极大地降低了细胞外基质降解、炎症细胞因子水平和血管中的白细胞/巨噬细胞浸润。NO-OA 给药可部分通过激活过氧化物酶体增殖物激活受体-γ（PPARγ），减少原发性和巨噬细胞系中各种生物刺激物触发的炎症、细胞因子分泌和细胞迁移。此外，NO-OA 的保护作用依赖于抑制巨噬细胞前列腺素 E2（PGE）诱导的 PGE 受体 4（EP4）cAMP 信号转导，已知该信号转导参与 AAA 的发生。
NO-OA 给药可预防 AAA 的形成和多因素的巨噬细胞激活。鉴于目前 NO-OA 正在进行 FDA 批准的 II 期临床试验，这些发现可能会加速该硝基脂肪酸在 AAA 治疗中的应用。
