Cole Marsha P, Rudolph Tanja K, Khoo Nicholas K H, Motanya Uche N, Golin-Bisello Franca, Wertz Jeffrey W, Schopfer Francisco J, Rudolph Volker, Woodcock Steven R, Bolisetty Subhashini, Ali Muhammad S, Zhang Jifeng, Chen Y Eugene, Agarwal Anupam, Freeman Bruce A, Bauer Philip M
Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pa., USA.
Circ Res. 2009 Nov 6;105(10):965-72. doi: 10.1161/CIRCRESAHA.109.199075. Epub 2009 Sep 24.
Fatty acid nitroalkenes are endogenously generated electrophilic byproducts of nitric oxide and nitrite-dependent oxidative inflammatory reactions. Existing evidence indicates nitroalkenes support posttranslational protein modifications and transcriptional activation that promote the resolution of inflammation.
The aim of this study was to assess whether in vivo administration of a synthetic nitroalkene could elicit antiinflammatory actions in vivo using a murine model of vascular injury.
The in vivo administration (21 days) of nitro-oleic acid (OA-NO(2)) inhibited neointimal hyperplasia after wire injury of the femoral artery in a murine model (OA-NO(2) treatment resulted in reduced intimal area and intima to media ratio versus vehicle- or oleic acid (OA)-treated animals,P<0.0001). Increased heme oxygenase (HO)-1 expression accounted for much of the vascular protection induced by OA-NO(2) in both cultured aortic smooth muscle cells and in vivo. Inhibition of HO by Sn(IV)-protoporphyrin or HO-1 small interfering RNA reversed OA-NO(2)-induced inhibition of platelet-derived growth factor-stimulated rat aortic smooth muscle cell migration. The upregulation of HO-1 expression also accounted for the antistenotic actions of OA-NO(2) in vivo, because inhibition of neointimal hyperplasia following femoral artery injury was abolished in HO-1(-/-) mice (OA-NO(2)-treated wild-type versus HO-1(-/-) mice, P=0.016).
In summary, electrophilic nitro-fatty acids induce salutary gene expression and cell functional responses that are manifested by a clinically significant outcome, inhibition of neointimal hyperplasia induced by arterial injury.
脂肪酸硝基烯烃是一氧化氮和亚硝酸盐依赖性氧化炎症反应内源性产生的亲电副产物。现有证据表明硝基烯烃支持促进炎症消退的翻译后蛋白质修饰和转录激活。
本研究旨在评估使用小鼠血管损伤模型，体内给予合成硝基烯烃是否能在体内引发抗炎作用。
在小鼠模型中，体内给予硝基油酸（OA-NO₂）21天可抑制股动脉钢丝损伤后的内膜增生（与载体或油酸（OA）处理的动物相比，OA-NO₂处理导致内膜面积和内膜与中膜比值降低，P<0.0001）。血红素加氧酶（HO）-1表达增加在很大程度上解释了OA-NO₂在体外培养的主动脉平滑肌细胞和体内诱导的血管保护作用。用Sn(IV)-原卟啉或HO-1小干扰RNA抑制HO可逆转OA-NO₂诱导的血小板衍生生长因子刺激的大鼠主动脉平滑肌细胞迁移的抑制作用。HO-1表达上调也解释了OA-NO₂在体内的抗狭窄作用，因为在HO-1基因敲除小鼠中，股动脉损伤后内膜增生的抑制作用消失（OA-NO₂处理的野生型小鼠与HO-1基因敲除小鼠相比，P=0.016）。
总之，亲电硝基脂肪酸诱导有益的基因表达和细胞功能反应，其临床显著结果是抑制动脉损伤诱导的内膜增生。
