Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University , Shenzhen , China.
Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , China.
Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):3704-3710. doi: 10.1080/21691401.2019.1665058.
Cardiovascular disease is recognized as a leading cause of death worldwide, but the risk of death is 2-3 times higher for individuals with diabetes. NLRP3 inflammasome activation is a leading pathway of vascular damage, and new treatment methods are needed to reduce NLRP3 inflammasome expression, along with a detailed understanding of how those treatments work. In a series of assays on human vascular endothelial cells that were exposed to high concentrations of free fatty acids (FFA) to induce a diabetes-like environment, we found a significant impact of cilostazol, a vasodilator widely used to treat blood flow problems and well-tolerated medication. To our knowledge, this study is the first to demonstrate the effects of cilostazol in primary human aortic endothelial cells. We found that cilostazol significantly reduced NLRP3 inflammasome activation, as well as the activity of other related and harmful factors, including oxidative stress, expression of NADPH oxidase 4 (NOX-4), thioredoxin-interacting protein (TxNIP), high mobility group box 1 (HMGB-1), interleukin 1β (IL-1β) and IL-18. Cilostazol also protected the functionality of sirtuin 1 (SIRT1), which serves to restrict NLRP3 inflammasome activity, when exposure to FFAs would have otherwise impaired its function. Thus, it appears that cilostazol's mechanism of action in reducing NLRP3 inflammasome activation is an indirect one; it protects SIRT1, which then allows SIRT1 to perform its regulatory job. Cilostazol has potential as an already-available, well-tolerated preventive medication that may alleviate some of the adverse vascular effects of living with diabetes. The findings of the present study lay the groundwork for further research on the potential of cilostazol as a safe and effective treatment against diabetic endothelial dysfunction and vacular disease.
心血管疾病被认为是全球范围内主要的死亡原因，但糖尿病患者的死亡风险要高出 2-3 倍。NLRP3 炎性小体的激活是血管损伤的主要途径，需要新的治疗方法来降低 NLRP3 炎性小体的表达，并详细了解这些治疗方法的作用机制。在一系列将人血管内皮细胞暴露于高浓度游离脂肪酸（FFA）以诱导类似糖尿病的环境的实验中，我们发现一种广泛用于治疗血流问题且耐受性良好的药物西洛他唑具有显著影响。据我们所知，这项研究首次证明了西洛他唑在原代人主动脉内皮细胞中的作用。我们发现，西洛他唑可显著降低 NLRP3 炎性小体的激活，以及其他相关有害因子的活性，包括氧化应激、NADPH 氧化酶 4（NOX-4）、硫氧还蛋白相互作用蛋白（TxNIP）、高迁移率族蛋白 1（HMGB-1）、白细胞介素 1β（IL-1β）和白细胞介素 18（IL-18）。当 FFA 暴露会损害 SIRT1 的功能时，西洛他唑还可以保护 SIRT1 的功能，SIRT1 可限制 NLRP3 炎性小体的活性。因此，西洛他唑降低 NLRP3 炎性小体激活的作用机制似乎是间接的；它可以保护 SIRT1，从而使 SIRT1 发挥其调节作用。西洛他唑具有作为一种已有的、耐受性良好的预防药物的潜力，可能会减轻糖尿病患者的一些不良血管影响。本研究的结果为进一步研究西洛他唑作为一种安全有效的治疗糖尿病内皮功能障碍和血管疾病的药物奠定了基础。
