Synthesis, Isomer Characterization, and Anti-Inflammatory Properties of Nitroarachidonate

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• 作者：Andr&eacute ; s Trostchansky ; Jos&eacute ; M. Souza ; Ana Ferreira ; Mariana Ferrari ; Fabiana Blanco ; Madia Trujillo ; Diego Castro ; Hugo Cerecetto ; Paul R. S. Baker ; Valerie B. O'Donnell ; Homero Rubbo
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：April 17, 2007
• 年：2007
• 卷：46
• 期：15
• 页码：4645 - 4653
• 全文大小：255K
• 年卷期：v.46,no.15(April 17, 2007)
• ISSN：1520-4995

文摘

Nitrated fatty acids (nitroalkenes) have been recently detected and quantified in cell membranesand human plasma. However, nitration of arachidonate (AA), that could redirect AA-dependent cellsignaling pathways, has not been studied in detail. Herein, we synthesized and determined for the firsttime the isomer distribution of nitroarachidonate (AANO₂) and demonstrate its ability to modulateinflammation. Synthesis of AANO₂ was achieved by AA treatment with sodium nitrite in acidic conditionsfollowing HPLC separation. Mass spectrometry (MS) analysis showed the characteristic MS/MS transitionof AANO₂ (m/z 348/301). Moreover, the IR signal at 1378.3 cm^-1 and NMR studies confirmed the presenceof mononitrated nitroalkenes. Positional isomer distribution was determined by NMR and MS fragmentationwith lithium; four major isomers (9-, 12-, 14-, and 15-AANO₂) were identified, which exhibited keyanti-inflammatory properties. These include their ability to release biologically relevant amounts of nitricoxide, induce cGMP-dependent vasorelaxation, and down-regulate inducible nitric oxide synthase (NOS2)expression during macrophage activation, providing unique structural evidence and novel regulatorysignaling properties of AANO₂.