Cystathionine γ lyase (CSE) is the major source of hydrogen sulfide-derived species (H₂S_n) in endothelial cells and plays an important role in protecting against atherosclerosis. Here we investigated the molecular mechanisms underlying the regulation of CSE expression in endothelial cells by fluid shear stress/flow. Fluid shear stress decreased CSE expression in human and murine endothelial cells and was negatively correlated with the transcription factor Krüppel-like factor (KLF) 2. CSE was identified as a direct target of the KLF2-regulated microRNA, miR-27b and high expression of CSE in native human plaque-derived endothelial cells, was also inversely correlated with KLF2 and miR-27b levels. One consequence of decreased CSE expression was the loss of Prx6 sulfhydration (on Cys47), which resulted in Prx6 hyperoxidation, decamerization and inhibition, as well as a concomitant increase in endothelial cell reactive oxygen species and lipid membrane peroxidation. H₂S_n supplementation in vitro was able to reverse the redox state of Prx6. Statin therapy, which is known to activate KLF2, also decreased CSE expression but increased CSE activity by preventing its phosphorylation on Ser377. As a result, the sulfhydration of Prx6 was partially restored in samples from plaque containing arteries from statin-treated donors. Taken together, the regulation of CSE expression by shear stress/disturbed flow is dependent on KLF2 and miR-27b. Moreover, in murine and human arteries CSE acts to maintain endothelial redox balance at least partly by targeting Prx6 to prevent its decamerization and inhibition of its peroxidase activity.

胱硫醚γ裂解酶（CSE）是硫化氢衍生物种（H ₂ S _n）在内皮细胞中发挥重要作用，并在预防动脉粥样硬化中起重要作用。在这里，我们研究了通过流体剪切应力/流动调节内皮细胞中CSE表达的分子机制。流体剪切应力降低了人和鼠内皮细胞中CSE的表达，并且与转录因子Krüppel样因子（KLF）2呈负相关。CSE被确定为KLF2调控的microRNA，miR-27b的直接靶标和高表达。天然人斑块来源的内皮细胞中的CSE也与KLF2和miR-27b水平呈负相关。CSE表达降低的结果之一是Prx6巯基化作用（在Cys47上）的丢失，这导致Prx6过度氧化，脱卡美化和抑制，以及内皮细胞活性氧和脂质膜过氧化的同时增加。H体外添加₂ S _n能够逆转Prx6的氧化还原状态。已知可激活KLF2的他汀类药物疗法也可降低CSE表达，但可通过阻止其在Ser377上的磷酸化来增加CSE活性。结果，在来自来自他汀类药物治疗的供体的含有动脉斑块的样品中，Prx6的巯基化得以部分恢复。总之，剪切应力/扰动流对CSE表达的调节取决于KLF2和miR-27b。此外，在鼠和人的动脉中，CSE至少部分地通过靶向Prx6来防止其脱金属化和抑制其过氧化物酶活性来维持内皮氧化还原平衡。