Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Arterioscler Thromb Vasc Biol. 2010 May;30(5):938-45. doi: 10.1161/ATVBAHA.109.201582. Epub 2010 Feb 18.
Inflammatory processes and foam cell formation are key determinants in the initiation and progression of atherosclerosis. Electrophilic nitro-fatty acids, byproducts of nitric oxide- and nitrite-dependent redox reactions of unsaturated fatty acids, exhibit antiinflammatory signaling actions in inflammatory and vascular cell model systems. The in vivo action of nitro-fatty acids in chronic inflammatory processes such as atherosclerosis remains to be elucidated.
Herein, we demonstrate that subcutaneously administered 9- and 10-nitro-octadecenoic acid (nitro-oleic acid) potently reduced atherosclerotic lesion formation in apolipoprotein E-deficient mice. Nitro-fatty acids did not modulate serum lipoprotein profiles. Immunostaining and gene expression analyses revealed that nitro-oleic acid attenuated lesion formation by suppressing tissue oxidant generation, inhibiting adhesion molecule expression, and decreasing vessel wall infiltration of inflammatory cells. In addition, nitro-oleic acid reduced foam cell formation by attenuating oxidized low-density lipoprotein-induced phosphorylation of signal transducer and activator of transcription-1, a transcription factor linked to foam cell formation in atherosclerotic plaques. Atherosclerotic lesions of nitro-oleic acid-treated animals also showed an increased content of collagen and alpha-smooth muscle actin, suggesting conferral of higher plaque stability.
These results reveal the antiatherogenic actions of electrophilic nitro-fatty acids in a murine model of atherosclerosis.
炎症过程和泡沫细胞形成是动脉粥样硬化起始和进展的关键决定因素。亲电硝基脂肪酸是一氧化氮和亚硝酸盐依赖的不饱和脂肪酸氧化还原反应的副产物，在炎症和血管细胞模型系统中表现出抗炎信号作用。硝基脂肪酸在动脉粥样硬化等慢性炎症过程中的体内作用仍有待阐明。
在此，我们证明皮下给予 9-和 10-硝基十八烯酸（硝基油酸）可有效减少载脂蛋白 E 缺陷小鼠的动脉粥样硬化病变形成。硝基脂肪酸不会调节血清脂蛋白谱。免疫染色和基因表达分析显示，硝基油酸通过抑制组织氧化剂生成、抑制粘附分子表达和减少炎症细胞向血管壁浸润来减轻病变形成。此外，硝基油酸通过减弱氧化低密度脂蛋白诱导的信号转导和转录激活因子 1 的磷酸化来减少泡沫细胞形成，该转录因子与动脉粥样硬化斑块中的泡沫细胞形成有关。硝基油酸处理动物的动脉粥样硬化病变还显示胶原和α-平滑肌肌动蛋白含量增加，表明斑块稳定性更高。
这些结果揭示了亲电硝基脂肪酸在动脉粥样硬化的小鼠模型中的抗动脉粥样硬化作用。
