Aspirin and HDAC regulation of endothelial function and vascular tone

说明（申请人提供）：低剂量乙酰水杨酸（阿司匹林）广泛用于治疗和预防血管疾病。阿司匹林可防止血小板活化和聚集，但也具有不依赖血小板的血管保护作用。阿司匹林促进内皮依赖性血管松弛，但其机制尚不完全清楚。该应用的主要假设是，低剂量阿司匹林可使内皮型一氧化氮合酶（eNOS）中的赖氨酸残基可逆乙酰化，从而刺激eNOS活性，促进内皮依赖性血管松弛。该应用的新颖之处在于：1)确定低剂量阿司匹林对eNOS的赖氨酸乙酰化作用，作为翻译后修饰，促进eNOS酶活性，从而促进内皮细胞NO生成；2)探索内源性赖氨酸去乙酰化酶组蛋白去乙酰化酶-3 （HDAC3）在逆转阿司匹林刺激的eNOS赖氨酸乙酰化，从而拮抗阿司匹林诱导的内皮细胞NO生成中的作用。这一建议的意义在于：1)确定了一种新的分子机制，通过这种机制，阿司匹林的心血管剂量可能具有血管保护作用；2)确定了一种潜在的可利用的内源性机制，可以拮抗阿司匹林对血管系统的作用。尽管低剂量阿司匹林在预防和治疗心血管疾病方面是有效的，但很大一部分服用阿司匹林的患者经历了动脉粥样硬化血栓事件，这强调了进一步了解阿司匹林在血管系统中的作用的重要性。通过观察eNOS的赖氨酸乙酰化作为低剂量阿司匹林对内皮功能影响的新机制，并通过鉴定内皮中阿司匹林的内源性拮抗剂，该应用可能为未来更好地利用这种广泛使用的药物的治疗潜力铺平道路。

DESCRIPTION (provided by applicant): Low-dose acetylsalicylic acid (aspirin) is widely used in the treatment and prevention of vascular disease. Aspirin prevents platelet activation and aggregation, but is also known to have platelet-independent vasoprotective effects. Aspirin promotes endothelium- dependent vasorelaxation but mechanisms by which it does so are not completely understood. The principal hypothesis of this application is that reversible acetylation of lysine residues in endothelial nitric oxide synthase (eNOS) by low-dose aspirin stimulates eNOS activity, and promotes endothelium-dependent vascular relaxation. The novelty of this application lies in 1) determining the role of lysine acetylation of eNOS by low-dose aspirin as a post-translational modification that promotes eNOS enzymatic activity and thereby endothelial NO production, and 2) exploring the role of the endogenous lysine deacetylase, histone deacetylase-3 (HDAC3), in reversing aspirin- stimulated lysine acetylation of eNOS and thereby antagonizing aspirin-induced endothelial NO production. The significance of this proposal lies in 1) identifying a novel molecular mechanism through which cardiovascular doses of aspirin may have vasoprotective effects, and 2) identifying a potentially exploitable endogenous mechanism that antagonizes the effect of aspirin on the vasculature. Although low-dose aspirin is effective in the prevention and treatment of cardiovascular disease, a significant proportion of patients on aspirin experience atherothrombotic events, underscoring the importance of further understanding how aspirin functions in the vasculature. This application, by looking at lysine acetylation of eNOS as a new mechanism for the effect of low-dose aspirin on endothelial function, and by identifying an endogenous antagonist to aspirin in the endothelium, may pave the way for future strategies that better harness the therapeutic potential of this widely used pharmaceutical. PUBLIC HEALTH RELEVANCE: Aspirin is widely used for the treatment and prevention of heart disease and has many beneficial effects on blood vessels. This research will explore whether aspirin chemically modifies nitric oxide synthase, a protein in blood vessels that improves vessel function and inhibits blood clot formation.