Wang Jie-Sian, Tsai Ping-Hsuan, Tseng Kuo-Feng, Lin Cheng-Li, Chen Fang-Yu, Chang Chiz-Tzung, Shen Ming-Yi
Graduate Institute of Biomedical Sciences, China Medical University, 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
Division of Nephrology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung 404327, Taiwan.
Antioxidants (Basel). 2024 Nov 29;13(12):1471. doi: 10.3390/antiox13121471.
There is limited understanding of the optimal duration and dosage of pentoxifylline (PTX) therapy required to achieve significant reductions in atherosclerotic cardiovascular disease (ASCVD) risk, particularly in patients with diabetic kidney disease (DKD). This study aimed to evaluate the impact of long-term PTX therapy on the risk of ASCVD in patients with DKD who do not have pre-existing cardiovascular disease, while also exploring potential vascular protective mechanisms. This retrospective cohort study included data from Taiwan's Ministry of Health and Welfare's Health and Welfare Data Science Center. In 2008-2019, we identified and analyzed a specific sample of 129,764 patients with DKD without established cardiovascular disease. Participants were categorized according to their PTX treatment regimen. Short-term PTX users (<763 days) had a greater risk of developing ASCVD than non-PTX users. However, those who used PTX for >763 days (long-term PTX treatment) had a significantly lower risk of ASCVD, with a 47% lower cumulative incidence. A dose-dependent reduction in apoptosis was observed via Klotho treatment in cultured human aortic endothelial cells following PTX treatment. Long-term PTX treatment (24 h) caused a higher reduction in HO-induced reactive oxygen species production and cell apoptosis than short-term PTX treatment (2 h). In the DKD mice model experiments, PTX reduced the ASCVD risk by increasing the Klotho levels to inhibit endothelial cell damage. These findings suggest that the cardiovascular and renoprotective benefits of PTX may be extended to primary prevention strategies for people with DKD.
对于己酮可可碱（PTX）治疗达到显著降低动脉粥样硬化性心血管疾病（ASCVD）风险所需的最佳疗程和剂量，人们了解有限，尤其是在糖尿病肾病（DKD）患者中。本研究旨在评估长期PTX治疗对无心血管疾病史的DKD患者发生ASCVD风险的影响，同时探索潜在的血管保护机制。这项回顾性队列研究纳入了来自台湾地区卫生福利部健康与福利数据科学中心的数据。在2008 - 2019年期间，我们识别并分析了129764例无心血管疾病的DKD患者的特定样本。参与者根据其PTX治疗方案进行分类。短期PTX使用者（<763天）发生ASCVD的风险高于非PTX使用者。然而，使用PTX超过763天（长期PTX治疗）的患者发生ASCVD的风险显著降低，累积发病率降低47%。在PTX处理后的培养人主动脉内皮细胞中，通过Klotho处理观察到凋亡呈剂量依赖性降低。长期PTX处理（24小时）比短期PTX处理（2小时）能更显著降低HO诱导的活性氧生成和细胞凋亡。在DKD小鼠模型实验中，PTX通过提高Klotho水平来抑制内皮细胞损伤，从而降低ASCVD风险。这些发现表明，PTX对心血管和肾脏的保护作用可能扩展到DKD患者的一级预防策略中。
