PDF(Pubmed)
Abstract：
Endothelial dysfunction (ED) serves as the pathological basis for various cardiovascular diseases. Guanosine triphosphate cyclopyrrolone 1 (GCH1) emerges as a pivotal protein in sustaining nitric oxide (NO) production within endothelial cells, yet it undergoes degradation under oxidative stress, contributing to endothelial cell dysfunction. Citronellal (CT), a monoterpenoid, has been shown to ameliorate endothelial dysfunction induced by in atherosclerosis rats. However, whether CT can inhibit the degradation of GCH1 protein is not clear. It has been reported that ubiquitination may play a crucial role in regulating GCH1 protein levels and activities. However, the specific E3 ligase for GCH1 and the molecular mechanism of GCH1 ubiquitination remain unclear. Using data-base exploration analysis, we find that the levels of the E3 ligase Smad-ubiquitination regulatory factor 2 (Smurf2) negatively correlate with those of GCH1 in vascular tissues and HUVECs. We observe that Smurf2 interacts with GCH1 and promotes its degradation via the proteasome pathway. Interestingly, ectopic Smurf2 expression not only decreases GCH1 levels but also reduces cell proliferation and reactive oxygen species (ROS) levels, mostly because of increased GCH1 accumulation. Furthermore, we identify BH 4/eNOS as downstream of GCH1. Taken together, our results indicate that CT can obviously improve vascular endothelial injury in Type 1 diabetes mellitus (T1DM) rats and reverse the expressions of GCH1 and Smurf2 proteins in aorta of T1DM rats. Smurf2 promotes ubiquitination and degradation of GCH1 through proteasome pathway in HUVECs. We conclude that the Smurf2-GCH1 interaction might represent a potential target for improving endothelial injury.
摘要：
内皮功能障碍（ED）是各种心血管疾病的病理基础。三磷酸鸟苷环吡咯烷酮1（GCH1）作为维持内皮细胞内一氧化氮（NO）产生的关键蛋白出现，然而它在氧化应激下降解，导致内皮细胞功能障碍。香茅醛(CT),一种单萜，已被证明可以改善动脉粥样硬化大鼠诱导的内皮功能障碍。然而,CT能否抑制GCH1蛋白降解尚不清楚。据报道，泛素化可能在调节GCH1蛋白水平和活性中起关键作用。然而,GCH1的特异性E3连接酶和GCH1泛素化的分子机制尚不清楚.使用数据库勘探分析，我们发现E3连接酶Smad-泛素化调节因子2（Smurf2）的水平与血管组织和HUVECs中GCH1的水平呈负相关。我们观察到Smurf2与GCH1相互作用并通过蛋白酶体途径促进其降解。有趣的是,异位Smurf2表达不仅降低GCH1水平，而且降低细胞增殖和活性氧（ROS）水平，主要是因为GCH1积累增加。此外，我们确定BH4/eNOS是GCH1的下游。一起来看,我们的结果表明，CT可以明显改善1型糖尿病（T1DM）大鼠的血管内皮损伤，并逆转T1DM大鼠主动脉中GCH1和Smurf2蛋白的表达。Smurf2通过蛋白酶体途径促进HUVECs中GCH1的泛素化和降解。我们得出结论，Smurf2-GCH1相互作用可能是改善内皮损伤的潜在靶标。
