Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana" University of Salerno, Via S. Allende, 84081, Baronissi, Italy.
IRCCS Neuromed, Vascular Physiopathology Unit, 86077, Pozzilli, Italy.
Cell Mol Life Sci. 2022 Jul 11;79(8):410. doi: 10.1007/s00018-022-04429-5.
Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here, we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers.
除了评估良好的风险因素外，心血管事件也可能与表观遗传和遗传改变有关，例如亚甲基四氢叶酸还原酶 (MTHFR) C677T 多态性。这种基因突变与同型半胱氨酸 (Hcy) 循环水平升高和心血管风险增加有关。然而，杂合子携带者即使 Hcy 水平正常，也会增加心血管意外的风险，这表明 MTHFR C677T 携带者中存在其他失调的过程。在这里，我们假设靶向 Sirtuin 1 (SIRT1) 可能是控制与 MTHFR 缺乏相关的心血管风险的一种替代机制。在给予白藜芦醇后，对携带 MTHFR C677T 等位基因的受试者进行血流介导的扩张 (FMD) 和透光比浊法测定。白藜芦醇是最强大的具有 SIRT1 激活特性的天然临床可用化合物，是最有效的天然临床可用化合物，具有 SIRT1 激活特性。具有正常 Hcy 水平的 MTHFR C677T 携带者表现出内皮功能障碍和增强的血小板聚集，这与 SIRT1 下调有关。白藜芦醇摄入对 SIRT1 活性的刺激能够克服这些异常，而不影响 Hcy 水平。在用白藜芦醇治疗后，杂合子 Mthfr 缺陷 (Mthfr) 小鼠模型中受损的内皮功能、出血时间和电丝诱导的血栓形成得到挽救。使用基于细胞的高通量多重筛选 (HTS) 测定法，鉴定出一种新型选择性合成 SIRT1 激活剂，即 ISIDE11。ISIDE11 对 Mthfr 小鼠的体外和体内治疗可挽救内皮血管舒张并减少电丝诱导的血栓形成，而 SIRT1 抑制剂可消除这些作用。此外，用 ISIDE11 处理的 MTHFR C677T 等位基因携带者的血小板显示出其典型的高反应性的正常化。这些结果表明 SIRT1 激活可作为控制 MTHFR 携带者的心血管和脑血管事件的新治疗策略。
