Biomarker Discovery Laboratory, Baker Heart and Diabetes Research Institute, Melbourne, Australia; Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia; Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Australia.
Vascul Pharmacol. 2021 Dec;141:106923. doi: 10.1016/j.vph.2021.106923. Epub 2021 Sep 29.
Protein-bound uremic toxins (PBUTs) have adverse effects on vascular function, which is imperative in the progression of cardiovascular and renal diseases. The role of sphingolipids in PBUT-mediated vasculo-endothelial pathophysiology is unclear. This study assessed the therapeutic potential of dihydroceramide desaturase 1 (Des1) inhibition, the last enzyme involved in de novo ceramide synthesis, to mitigate the vascular effects of the PBUT indoxyl sulfate (IS). Rat aortic rings were isolated and vascular reactivity was assessed in organ bath experiments followed by immunohistochemical analyses. Furthermore, cultured human aortic endothelial cells were assessed for phenotypic and mechanistic changes. Inhibition of Des1 by a selective inhibitor CIN038 (0.1 to 0.3 μM) improved IS-induced impairment of vasorelaxation and modulated immunoreactivity of oxidative stress markers. Des1 inhibition also reversed IS-induced reduction in endothelial cell migration (1.0 μM) by promoting the expression of angiogenic cytokines and reducing inflammatory and oxidative stress markers. These effects were associated with a reduction of TIMP1 and the restoration of Akt phosphorylation. In conclusion, Des1 inhibition improved vascular relaxation and endothelial cell migration impaired by IS overload. Therefore, Des1 may be a suitable intracellular target to mitigate PBUT-induced adverse vascular effects.
蛋白结合性尿毒症毒素 (PBUT) 对血管功能有不良影响，而这在心血管和肾脏疾病的进展中至关重要。鞘脂类物质在 PBUT 介导的血管内皮生理病理学中的作用尚不清楚。本研究评估了二氢神经酰胺去饱和酶 1 (Des1) 抑制的治疗潜力，Des1 是从头合成神经酰胺的最后一种酶，以减轻蛋白结合性尿毒症毒素吲哚硫酸酯 (IS) 的血管作用。分离大鼠主动脉环，并在器官浴实验中评估血管反应性，随后进行免疫组织化学分析。此外，还评估了培养的人主动脉内皮细胞的表型和机制变化。选择性抑制剂 CIN038（0.1 至 0.3 μM）抑制 Des1 可改善 IS 诱导的血管舒张功能障碍，并调节氧化应激标志物的免疫反应性。Des1 抑制还通过促进血管生成细胞因子的表达和减少炎症和氧化应激标志物来逆转 IS 诱导的内皮细胞迁移减少（1.0 μM）。这些作用与 TIMP1 的减少和 Akt 磷酸化的恢复有关。总之，Des1 抑制可改善 IS 过载引起的血管舒张和内皮细胞迁移受损。因此，Des1 可能是减轻 PBUT 诱导的不良血管作用的合适的细胞内靶点。
