Cell signaling actions mediated by reduction-oxidation (redox)-dependent post-translational modifications include oxidation, glutathionylation, S-nitrosation, and alkylation reactions. These reactions intimately link metabolic and inflammatory status with changes in cell and organ function, since many enzymes, receptors and transcriptional regulatory proteins mediating metabolic and inflammatory responses contain functionally- significant hyperreactive Cys moieties. We now know that nitrite (NO2-) and nitrate (NO3-) are metabolized by commensal bacteria, metalloproteins, and digestive processes, yielding nitric oxide (NO) and secondary nitrogen oxides that elicit unique redox signaling responses via nitrosation, nitration and oxidation reactions. The nature and amounts of various nitrogen oxides are dependent on inflammatory status, diet, acidic microenvironments and NO3--reducing enterosalivary bacterial populations. Many of these products are chemically reactive and generate protein NO-heme complexes, protein Cys-NO adducts (RSNO), and electrophilic fatty acid nitroalkenes (NO2-FA) that readily and reversibly alkylate susceptible protein thiols. The cGMP-independent pleiotropic signaling actions of NO2-FAs induce adaptive tissue responses that include beneficial shifts in adipokine and cytokine expression, restoration of insulin sensitivity and the attenuation of right ventricular end systolic pressure (RVESP). This motivated us to hypothesize that the promotion of nitro- fatty acid signaling alleviates metabolic syndrome-induced hypertension and its pulmonary complications. To test this concept, a de-risked new drug strategy is evaluated by pursuing two mechanistically-revealing model system and clinically-based specific aims: 1. Define the molecular targets, biochemical responses and physiological actions of a) the dietary NO2-FA precursors (NO2-, NO3-, conjugated linoleic acid) and b) pure NO2-FA in rodent models of obesity-induced pulmonary hypertension. 2. Evaluate the clinical responses of Group 1 pulmonary arterial hypertension patients to the orally administered NO2-FA, 10-nitro-octadec-9-enoic acid (NO2-OA). Preliminary studies reveal that NO2-FA-mediated PTMs will promote salutary responses, as NO2-FA have already undergone extensive preclinical toxicology and pharmacokinetics evaluation and are in FDA-approved Phase 1 testing of both IV and oral formulations in humans. The pulmonary vascular responses to NO2-FA are anticipated to be more efficacious than many single-target drugs, because of the pleiotropic signaling actions of NO2-FA.
The research plan is designed to test the beneficial metabolic and anti-inflammatory actions of an endogenously present class of modified fats, termed nitro-fatty acids. These molecules are also present in plants and natural oils, and are formed during digestion and inflammatory reactions. Because of the potent tissue-protective actions of nitro-fatty acids, they are being developed as new drug candidates and, in this proposed study, as therapeutic agents for treating pulmonary hypertension.
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