It is becoming increasingly evident that nitric oxide (NO)-derived reactive species (RNS) mediate diverse vascular cell signaling and pathogenic processes. RNS oxidize and nitrate carbohydrates, DNA, protein, and unsaturated fatty acids. Although significant understanding exists regarding the -NO-dependent nitration of protein (e.g. tyrosine residues to 3-nitrotyrosine), little is known related to nitrated lipids. Nitrated fatty acids (nitroalkenes) are clinically abundant molecules present in the human circulation at micromolar levels and are now appreciated as a novel class of signaling molecules. The physiological relevance and mechanisms of signal transduction induced by nitroalkenes need to be better defined. Of significance, we have recently identified nitrolinoleic acid (LNO2) as a potent peroxisome proliferator-activated receptor (PPAR) gamma ligand, suggesting that the PPARgamma-signaling pathway will be a key mediator of LNO2-regulated effects. Preliminary studies document that LNO2 exerts pro-apoptotic and growth-inhibitory effects in VSMC. In addition, exogenous administration of LNO2 inhibits vascular lesion formation in balloon-injured rat carotid arteries. Furthermore, computer modeling of LNO2/PPARgamma interaction reveals that R288 and C285 in the PPARgamma ligand binding domain may interact directly with the NO2 moiety of LNO2. These results support the working hypothesis that activation of PPARgamma by LN02 inhibits vascular lesion formation by decreasing VSMC proliferation and promoting apoptosis. This hypothesis will be tested by systematically implementing structure-function analysis of LNO2/PPARgamma pathway with both a loss- and gain-of-function strategy using both in vitro and in vivo model systems. Specifically, we will: 1). Determine the molecular mechanisms mediating LNO2 activation of PPARgamma; 2). Define the role of the LNO2-mediated PPARgamma signaling in the regulation of VSMC proliferation and survival; 3). Define whether LNO2-dependent PPARgamma activation serves to inhibit vascular lesion formation. This proposed research plan will provide important insights into the signaling actions of the LNO2/PPARgamma pathway as a critical inhibitor of vascular inflammation and lesion formation. Advances in understanding the mechanisms of endogenous PPARgamma modulation will provide novel therapeutic strategies for treating obesity/diabetes and cardiovascular disease.
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