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）是内皮细胞中硫化氢衍生物质（H ₂ S _n ）的主要来源，在预防动脉粥样硬化中发挥着重要作用。在这里，我们研究了流体剪切应力/流动调节内皮细胞 CSE 表达的分子机制。流体剪切应力降低人和鼠内皮细胞中的 CSE 表达，并与转录因子 Krüppel 样因子 (KLF) 2 呈负相关。CSE 被确定为 KLF2 调节的 microRNA、miR-27b 和高表达的 microRNA 的直接靶标。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 表达减少的后果之一是 Prx6 硫氢化作用（Cys47 上）的丧失，从而导致 Prx6 过度氧化、去分子化和抑制，以及伴随的内皮细胞活性氧和脂质膜过氧化的增加。体外补充H ₂ S _n能够逆转Prx6 的氧化还原状态。他汀类药物治疗已知可激活 KLF2，也可降低 CSE 表达，但通过阻止其 Ser377 磷酸化来增加 CSE 活性。结果，在含有他汀类药物治疗的供体动脉斑块的样本中，Prx6 的硫化作用得到了部分恢复。综上所述，剪切应力/扰动流对 CSE 表达的调节依赖于 KLF2 和 miR-27b。此外，在小鼠和人类动脉中，CSE 至少部分通过靶向 Prx6 来维持内皮氧化还原平衡，以防止其去分子化和抑制其过氧化物酶活性。