Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY.
J Lipid Res. 2018 Jan;59(1):69-78. doi: 10.1194/jlr.M079731. Epub 2017 Nov 22.
Vascular calcification is the deposition of mineral in the artery wall by vascular smooth muscle cells (VSMCs) in response to pathological stimuli. The process is similar to bone formation and is an independent risk factor for cardiovascular disease. Given that ceramide and sphingosine 1-phosphate (S1P) are involved in cardiovascular pathophysiology and biomineralization, their role in VSMC matrix mineralization was investigated. During phosphate-induced VSMC mineralization, endogenous S1P levels increased accompanied by increased sphingosine kinase (SK) activity and increased mRNA expression of SK1 and SK2. Consistent with this, mineralization was increased by exogenous S1P, but decreased by C2-ceramide. Mechanistically, exogenous S1P stimulated ezrin-radixin-moesin (ERM) phosphorylation in VSMCs and ERM phosphorylation was increased concomitantly with endogenous S1P during mineralization. Moreover, inhibition of acid sphingomyelinase and ceramidase with desipramine prevented increased S1P levels, ERM activation, and mineralization. Finally, pharmacological inhibition of ERM phosphorylation with NSC663894 decreased mineralization induced by phosphate and exogenous S1P. Although further studies will be needed to verify these findings in vivo, this study defines a novel role for the SK-S1P-ERM pathways in phosphate-induced VSMC matrix mineralization and shows that blocking these pathways with pharmacological inhibitors reduces mineralization. These results may inform new therapeutic approaches to inhibit or delay vascular calcification.
血管钙化是血管平滑肌细胞（VSMCs）在病理刺激下在动脉壁中沉积矿物质的过程。该过程类似于骨形成，是心血管疾病的独立危险因素。鉴于神经酰胺和鞘氨醇 1-磷酸（S1P）参与心血管病理生理学和生物矿化，研究了它们在 VSMC 基质矿化中的作用。在磷酸盐诱导的 VSMC 矿化过程中，内源性 S1P 水平增加，同时鞘氨醇激酶（SK）活性增加，SK1 和 SK2 的 mRNA 表达增加。与此一致，外源性 S1P 增加矿化，但 C2-神经酰胺减少矿化。在机制上，外源性 S1P 刺激 VSMCs 中的 ezrin-radixin-moesin（ERM）磷酸化，并且在矿化过程中，内源性 S1P 同时增加 ERM 磷酸化。此外，用去甲丙咪嗪抑制酸性鞘磷脂酶和神经酰胺酶可防止 S1P 水平升高、ERM 激活和矿化。最后，用 NSC663894 抑制 ERM 磷酸化可减少磷酸盐和外源性 S1P 诱导的矿化。尽管还需要进一步的体内研究来验证这些发现，但本研究定义了 SK-S1P-ERM 途径在磷酸盐诱导的 VSMC 基质矿化中的新作用，并表明用药理抑制剂阻断这些途径可减少矿化。这些结果可能为抑制或延迟血管钙化提供新的治疗方法。
