Aspirin and HDAC regulation of endothelial function and vascular tone

描述(申请人提供)：小剂量的乙酰水杨酸(阿司匹林)被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，但也被认为具有非依赖于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，但其作用机制尚不完全清楚。这一应用的主要假设是，内皮型一氧化氮合酶(ENOS)中赖氨酸残基被小剂量阿司匹林可逆地乙酰化，刺激eNOS活性，促进内皮依赖性血管松弛。这一应用的新颖之处在于：1)确定小剂量阿司匹林对eNOS赖氨酸乙酰化的作用，作为翻译后修饰，促进eNOS的酶活性，从而促进内皮NO的产生；2)探索内源性赖氨酸脱乙酰酶-组蛋白脱乙酰酶-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NO产生中的作用。这一建议的意义在于：1)确定一种新的分子机制，通过该机制，心血管剂量的阿司匹林可能具有血管保护作用；2)确定一种潜在的可利用的内源性机制，该机制可拮抗阿司匹林对血管系统的影响。虽然小剂量阿司匹林在预防和治疗心血管疾病方面是有效的，但服用阿司匹林的患者中有相当一部分人经历了动脉粥样硬化血栓事件，这突显了进一步了解阿司匹林在血管系统中如何发挥作用的重要性。通过将eNOS的赖氨酸乙酰化作为小剂量阿司匹林影响内皮功能的新机制，以及通过确定内皮细胞中阿司匹林的内源性拮抗剂，这一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.