Friday, April 19, 2024
4/19/2024
PROJECT SUMMARY Organic nitrate esters are long-appreciated treatments for cardiovascular disease (CVD), leading causes of death worldwide. Of note, organic nitrates have never been detected biologically, and their vasodilatory effects are attenuated by the development of nitrate tolerance and endothelial dysfunction, highlighting an urgent need for alternative therapies. In this context, dietary interventions reduce CVD incidence and mortality. While benefits of the dietary interventions are clinically well documented, new data continues to emerge as to the contributions of individual dietary constituents in mediating beneficial downstream responses. Consumption of fruits, vegetables, meat, and dairy products provides a rich source of conjugated linoleic acid (CLA) and the inorganic anions nitrite (NO2-), and nitrate (NO3-). Strong evidence reveals that NO2- and NO3- are readily transformed by metabolic and inflammatory conditions promoting nitration of CLA and yielding electrophilc nitroalkene derivatives (NO2-FA), which induce reversible alkylation of nucleophilic cysteine (Cys) residues with consequent post-translational modification (PTM) of many functionally-significant regulatory proteins. Preclinical and clinical data affirm that NO2-FA induce pleiotropic adaptive and anti-inflammatory gene expression responses. We recently reported that the acidic gastric environment and the conjugated double bound of CLA results in a novel NO2--mediated unsaturated fatty acid nitration mechanism that is critical for generating organic nitrate-containing fatty acid derivatives, termed nitro-nitrate fatty acids (NO2-ONO2-FA). Preliminary data indicates that NO2-ONO2- FA: a) are not only endogenously-generated in vivo by digestive reactions of CLA + NO2- but also upon ex vivo myocardial I/R injury, b) survive intestinal absorption, are incorporated into chylomicron triglycerides and reach the systemic circulation, c) are non-electrophilic that then decay to an electrophilic NO2-FA product after releasing secondary nitrogen oxides and d) can induce concerted salutary PTM effects and guanylate cyclase activation. From this insight, it is now hypothesized that NO2-ONO2-FA derivatives promote vasodilation and inhibit cardiovascular inflammatory responses via both cGMP-dependent and cGMP-independent signaling actions. The rationale for pursuing this project is to define the biochemical formation and unique PK and signaling actions of NO2-ONO2-FA, that current data support is a small molecule mediator that displays the pharmacology of both organic nitrates and Cys-reactive electrophiles. We also better define the scope of endogenous products stemming from the metabolic reactions of both a healthy diet and inflammation. The goals of the proposal are: 1) to define the metabolic and inflammatory generation and PK of NO2-ONO2-FA and 2) to quantify the in vitro and in vivo cardiovascular responses to NO2-ONO2-FA in the context of both vasodilatory and vasoprotective cGMP-dependent and cGMP-independent signaling. Successful completion of the proposed research plan can lay the foundation for a safe pharmacological strategy targeting inflammatory-related CVD.
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