Laboratory of Vascular Biology and Drug Development, INDICYO Program, Institut Pasteur de Montevideo, Montevideo, Uruguay.
Departmento de Química Orgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay.
Br J Pharmacol. 2019 Mar;176(6):757-772. doi: 10.1111/bph.14561. Epub 2019 Feb 3.
Atherosclerosis is characterized by chronic low-grade inflammation with concomitant lipid accumulation in the arterial wall. Anti-inflammatory and anti-atherogenic properties have been described for a novel class of endogenous nitroalkenes (nitrated-unsaturated fatty acids), formed during inflammation and digestion/absorption processes. The lipid-associated antioxidant α-tocopherol is transported systemically by LDL particles including to the atheroma lesions. To capitalize on the overlapping and complementary salutary properties of endogenous nitroalkenes and α-tocopherol, we designed and synthesized a novel nitroalkene-α-tocopherol analogue (NATOH) to address chronic inflammation and atherosclerosis, particularly at the lesion sites.
We synthesized NATOH, determined its electrophilicity and antioxidant capacity and studied its effects over pro-inflammatory and cytoprotective pathways in macrophages in vitro. Moreover, we demonstrated its incorporation into lipoproteins and tissue both in vitro and in vivo, and determined its effect on atherosclerosis and inflammatory responses in vivo using the Apo E knockout mice model.
NATOH exhibited similar antioxidant capacity to α-tocopherol and, due to the presence of the nitroalkenyl group, like endogenous nitroalkenes, it exerted electrophilic reactivity. NATOH was incorporated in vivo into the VLDL/LDL lipoproteins particles to reach the atheroma lesions. Furthermore, oral administration of NATOH down-regulated NF-κB-dependent expression of pro-inflammatory markers (including IL-1β and adhesion molecules) and ameliorated atherosclerosis in Apo E knockout mice.
In toto, the data demonstrate a novel pharmacological strategy for the prevention of atherosclerosis based on a creative, natural and safe drug delivery system of a non-conventional anti-inflammatory compound (NATOH) with significant potential for clinical application.
动脉粥样硬化的特征是慢性低度炎症，伴有动脉壁内脂质堆积。新型内源性硝烯类（硝化不饱和脂肪酸）具有抗炎和抗动脉粥样硬化特性，它们在炎症和消化/吸收过程中形成。脂相关抗氧化剂α-生育酚通过包括 LDL 颗粒在内的全身系统运输，包括运输到动脉粥样硬化病变部位。为了利用内源性硝烯类和α-生育酚重叠和互补的有益特性，我们设计并合成了一种新型硝烯-α-生育酚类似物（NATOH），以解决慢性炎症和动脉粥样硬化问题，特别是在病变部位。
我们合成了 NATOH，测定了其亲电性和抗氧化能力，并研究了其在体外巨噬细胞中对促炎和细胞保护途径的影响。此外，我们证明了它在体外和体内都能整合到脂蛋白和组织中，并使用 Apo E 基因敲除小鼠模型确定了它对动脉粥样硬化和炎症反应的体内作用。
NATOH 表现出与α-生育酚相似的抗氧化能力，并且由于存在硝烯基，与内源性硝烯类一样，它具有亲电反应性。NATOH 被体内整合到 VLDL/LDL 脂蛋白颗粒中，到达动脉粥样硬化病变部位。此外，口服 NATOH 可下调 NF-κB 依赖性促炎标志物（包括 IL-1β 和粘附分子）的表达，并改善 Apo E 基因敲除小鼠的动脉粥样硬化。
总的来说，这些数据证明了一种基于创新、天然和安全药物输送系统的新型预防动脉粥样硬化的药理学策略，该系统具有一种非传统抗炎化合物（NATOH）的显著临床应用潜力。
