Nitro–Fatty Acids Reduce Atherosclerosis in Apolipoprotein E–Deficient Mice

Abstract

Objective-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. Methods and Results-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 ␣-smooth muscle actin, suggesting conferral of higher plaque stability. Conclusion-These

Conjugated Linoleic Acid Is a Preferential Substrate for Fatty Acid Nitration

“…The consideration of the endogenous generation, metabolism, and reactions of electrophilic NO 2 -FA is of relevance because these species potently limit inflammation via multiple mechanisms, including PPAR␥ activation, the inhibition of expression of pro-inflammatory NF-B-regulated genes, and up-regulation of HO-1 and other phase 2 genes regulated by Keap1/Nrf2. Thus, in murine models of metabolic and inflammatory injury, fatty acid nitroalkene administration at nanomolar concentrations prevents restenosis after vessel injury (49), limits weight gain and loss of insulin sensitivity in murine models of metabolic syndrome (14), protects against ischemia-reperfusion injury (17,47,50), reduces plaque formation in a rodent model of atherosclerosis (51), and inhibits the onset of chemically induced inflammatory bowel disease (52).…”

Nitro-fatty acid pharmacokinetics in the adipose tissue compartment

“…The electrophilic properties of NO 2 -FA induce anti-inflammatory and cytoprotective actions via reversible posttranslational modification of transcriptional regulatory proteins, such as NF-kB, Keap1/ Nrf2, and PPAR-, and enzymes such as xanthine oxidoreductase and sEH (6)(7)(8)(36)(37)(38). Beneficial metabolic and anti-inflammatory effects of NO 2 -FAs have been shown in animal models of fibrosis, atherosclerosis, renal and cardiac ischemia reperfusion, restenosis, and diabetes (12,(39)(40)(41)(42)(43)(44). in nitro-alkane metabolites could reflect their cellular reuptake and esterification into complex lipids.…”

Protective Effects of 10-nitro-oleic Acid in a Hypoxia-Induced Murine Model of Pulmonary Hypertension

“…Because cysteine residues are frequently functionally significant constituents of transcriptional regulatory proteins and enzymes, both adaptive and toxicological responses might occur on cysteine alkylation, and NO 2 -FA would be expected to influence numerous signaling pathways (12). Besides exhibiting potent anti-inflammatory effects by inhibition of NF-kB (11,14) and the signal transducer and activator of transcription (STAT) (15,16), activation of the Keap1/Nrf2 system (17), and induction of heat shock factor (18), NO 2 -FA also display beneficial metabolic effects by serving as partial agonists of peroxisome proliferatoractivated receptors (19,20). In a murine model of vascular injury, NO 2 -FA inhibited aortic vascular smooth muscle cell proliferation and migration via activation of heme oxygenase 1 expression and catalytic activity, thus significantly reducing neointima formation (21).…”