Citronellal improves endothelial dysfunction by affecting the stability of the GCH1 protein  

作　　者：Yaqi Guo Huadong Que Bulei Chen Chunyan Chao Shanshan Li Shuang Guo Yaling Yin Huanhuan Wang Moli Zhu Peng Li 

机构地区：[1]SanQuan Medical College,Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology,Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention,School of Basic Medical Sciences,College of Pharmacy,Xinxiang Medical University,Xinxiang 453003,China [2]Huang Huai University,Zhumadian 463000,China [3]Hubei Key Laboratory of Diabetes and Angiopathy,Hubei University of Science and Technology,Xianning 437100,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第7期963-972,共10页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the Henan Province Outstanding Youth Science Fund Project(No.242300421025);the National Natural Science Foundation of China(No.82271460);the Research Foundation of Henan Province(No.HNGD2022067);the National High-End Foreign Expert Recruitment Plan of China(No.G2022026006L);the Research Foundation of Xinxiang Medical University(No.XYBSKYZZ202202).

摘　　要：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.

关 键 词：CITRONELLAL endothelial dysfunction SMURF2 degradation 

分 类 号：Q51[生物学—生物化学]