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975863 
Journal Article 
Abstract 
Activation of endothelial nitric oxide synthase and heme oxygenase 1 expression in vasculature by nitro-fatty acids 
Khoo, N; Golin-Bisello, F; Patel, RP; Freeman, BA 
2008 
Yes 
Free Radical Biology and Medicine
ISSN: 0891-5849
EISSN: 1873-4596 
45 
Suppl. 
S32-S32 
English 
is part of a larger document 3452652 SFRBM's 15th Annual Meeting: Program and Abstracts
An early manifestation of vascular disease is endothelial dysfunction, often a consequence of a reduction in nitric oxide (NO) bioavailability. Reactive oxygen species mediate reduction of NO bioavailability, with secondary oxidized and nitrated byproducts of these reactions contributing to the pathogenesis of numerous cardiovascular diseases (CVDs). Herein we report that redox-derived nitro-fatty acids (NO2-FA) activate expression of endothelial nitric oxide synthase (eNOS) and heme oxygenase 1 (HO-1) in the vasculature, thus transducing vascular protective effects associated with enhanced NO production. NO2-FA treatment increased, in a dose-dependent manner, eNOS mRNA and protein expression (>3- and >2.5-fold, respectively) in cultured endothelial cells (ECs), 6 to 24 h after treatment. Cell viability was not significantly altered and HO-1 expression was also enhanced (>15-fold for mRNA and protein). Furthermore, HO-1 levels also significantly increased dose- and time-dependently in vascular smooth muscle cells (VSMCs). Appreciating that phosphorylation of eNOS at several regulatory sites plays an important role in enzyme activity and can result in a 2-3 fold increase in NO production, ECs were treated with 0.1-5 μM NO2-FAs, which stimulated the phosphorylation of eNOS at Ser1179 and induced concomitant dephosphorylation at Thr497. These post-translational modifications of eNOS, in concert with elevated eNOS gene expression contributed to an increase in cellular NO production as measured by ozone chemiluminescence. Upstream stimulation of eNOS phosphorylation was dependent upon the phosphatidylinositol 3-kinase-Akt pathway and the p38 mitogen-activated protein kinase pathways. In aggregate, NO2-FA-induced eNOS and HO-1 expression by ECs and HO-1 upregulation by VSMCs may have beneficial effects on endothelial dysfunction and provide a new strategy for therapy associated with CVD. While oxidized lipids and lipoproteins exacerbate inflammatory reactions in the vasculature, in stark contrast the nitration of polyunsaturated fatty acids and complex lipids yield electrophilic products that exhibit pluripotent anti-inflammatory signaling capabilities acting via both cGMP-dependent and -independent mechanisms. 
Society for Free Radical Biology and Medicine 15th Annual Meeting 
Indianapolis, IN 
November 19-23, 2008