Nitro-nitrate fatty acid derivatives as novel cGMP-dependent and cGMP-independent signaling mediators

硝基硝酸脂肪酸衍生物作为新型 cGMP 依赖性和 cGMP 独立信号传导介质

基本信息

  • 批准号:
    10583877
  • 负责人:
  • 金额:
    $ 60.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-01 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

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.
项目摘要 有机硝酸酯是心血管疾病(CVD)的长期受欢迎的治疗方法,心血管疾病是导致心血管疾病的主要原因。 全世界的死亡值得注意的是,有机硝酸盐从未被生物学检测到,其血管舒张作用 由于硝酸盐耐受性和内皮功能障碍的发展而减弱,突出了迫切需要 替代疗法在这种情况下,饮食干预可以降低CVD的发病率和死亡率。虽然好处 的饮食干预临床上有很好的记录,新的数据不断出现的贡献, 个别饮食成分在介导有益的下游反应。食用水果, 蔬菜、肉类和乳制品提供了丰富的共轭亚油酸(CLA)和无机脂肪酸的来源。 亚硝酸根(NO2−)和硝酸根(NO3−)。强有力的证据表明,NO2-和NO3-很容易转化为 通过代谢和炎症条件促进CLA的硝化并产生亲电硝基烯烃 衍生物(NO2-FA),可诱导亲核半胱氨酸(Cys)残基的可逆烷基化,从而 翻译后修饰(PTM)的许多功能重要的调节蛋白。临床前和临床 数据证实NO2-FA诱导多效性适应性和抗炎基因表达应答。我们 最近报道,酸性胃环境和共轭双键的共轭亚油酸导致一种新的 NO2−-介导的不饱和脂肪酸硝化机制,对于生成含有机硝酸盐的 脂肪酸衍生物,称为硝基硝酸酯脂肪酸(NO2-ONO 2-FA)。初步数据表明,NO2-ONO 2- FA:a)不仅在体内通过CLA + NO2−的消化反应内源性产生,而且在离体时也是如此。 心肌I/R损伤,B)存活于肠吸收,被掺入乳糜微粒甘油三酯中并达到 体循环,c)是非亲电性,然后在 释放次生氮氧化物和d)可以诱导协同的有益PTM效应和鸟苷酸环化酶 activation.从这一观点出发,现在假设NO2-ONO 2-FA衍生物促进血管舒张, 通过cGMP依赖性和cGMP非依赖性抑制心血管炎症反应 信号动作。追求这个项目的基本原理是定义生物化学形成和独特的PK 和NO2-ONO 2-FA的信号传导作用,目前的数据支持是一个小分子介体, 有机硝酸盐和Cys反应性亲电体的药理学。我们还更好地定义了 来自健康饮食和炎症的代谢反应的内源性产物。的目标 的建议是:1)定义NO2-ONO 2-FA的代谢和炎症产生以及PK,2) 在血管舒张和血管舒张的背景下,定量体外和体内对NO2-ONO 2-FA的心血管反应, 以及血管保护性cGMP依赖性和cGMP非依赖性信号传导。圆满完成拟议的 研究计划可以为针对炎症相关CVD的安全药理学策略奠定基础。

项目成果

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