Abstract:Objective: To investigate the role of endoplasmic reticulum-associated degradation-enhancing α-glucosidase-like protein 1 (EDEM1) and activating transcription factor 6 (ATF6) in the development of intracranial aneurysms (IA). Methods: Forty IA patients and 40 healthy subjects were recruited. Serum was collected from both groups, and ATF6 levels were detected by ELISA. IA patients were divided into mild, moderate, and severe disease groups according to Hunt-Hess and Fisher grading. ATF6 levels in the serum of the three groups were compared. si-EDEM1 and si-NC were transfected into HCAECs cells, and the cells were divided into si-EDEM1 and si-NC groups. Western blot was used to detect the expression levels of EDEM1 and ATF6 proteins in the two groups of cells, and CCK-8 assay was used to detect the proliferation of the two groups of cells. Co-immunoprecipitation was used to detect the interaction between EDEM1 and ATF6. si-ATF6 and si-NC were transfected into HCAECs cells, and the cells were divided into si-ATF6 and si-NC groups. Western blot was used to detect the expression levels of EDEM1 and ATF6 proteins in the two groups of cells, and CCK-8 assay was used to detect the proliferation of the two groups of cells. Results: Compared with healthy subjects, the serum ATF6 level in IA patients was increased (P<0.05). The ATF6 level increased sequentially in the mild, moderate, and severe disease groups (P<0.05). Compared with the si-NC group, the expression levels of EDEM1 and ATF6 proteins were decreased in the si-EDEM1 group cells, and the proliferation of the cells was decreased (P<0.05). EDEM1 and ATF6 interact with each other. Compared with the si-NC group, the expression level of ATF6 protein was decreased in the si-ATF6 group cells, and the proliferation of the cells was decreased (P<0.05). Conclusion: EDEM1 promotes the proliferation of arterial endothelial cells by stabilizing ATF6 and is associated with the progression of IA.
[1] Mathioudakis N,Georgakopoulou VE,Paterakis K,et al.Effect of circulating miR126 levels on intracranial aneurysms and their predictive value for the rupture of aneurysms:a systematic review and metaanalysis[J].Exp Ther Med,2023,26(2):411. [2] Nowakowska-Gotacka J,Czapiewska J,Sominka H,et al.EDEM1 regulates amyloid precursor protein (APP) metabolism and amyloid-β production[J].Int Mol Sci,2021,23(1):117. [3] Stengel ST,Fazio A,Lipinski S,et al.Activating transcription factor 6 mediates inflammatory signals in intestinal epithelial cells upon endoplasmic reticulum stress[J].Gastroenterology,2020,159(4):1357-1374. [4] Shen Y,Li R,Yu S,et al.Activation of the ATF6 (activating transcription factor 6) signaling pathway in neurons improves outcome after cardiac arrest in mice[J].Am Heart Assoc,2021,10(12):20216. [5] Zhang HM,Qiu Y,Zhao G,et al.Cleavage and degradation of EDEM1 promotes coxsackievirus B3 replication via ATF6a-mediated unfolded protein response signalling[J].Cell Microbiol,2020,22(7):e13198. [6] Chen HY,Elmer J,Zafar SF,et al.Combining transcranial doppler and EEG data to predict delayed cerebral ischemia after subarachnoid hemorrhage[J].Neurology,2022,98(5):e459-e469. [7] Marbacher S,Niemela M,Hernesniemi J,et al.Recurrence of endovascularly and microsurgically treated intracranial aneurysms-review of the putative role of aneurysm wall biology[J].Neurosurg Rev,2019,42(1):49-58. [8] Li C,Pan B,Liu X,et al.Long intergenic non-coding RNA LINC00485 exerts tumor-suppressive activity by regulating miR-581/EDEM1 axis in colorectal cancer[J].Aging (Albany NY),2021,13(3):3866-3885. [9] Tumanovska LV,Swanson RJ,Serebrovska ZO,et al.Cholesterol enriched diet suppresses ATF6 and PERK and upregulates the IRE1 pathways of the unfolded protein response in spontaneously hypertensive rats:relevance to pathophysiology of atherosclerosis in the setting of hypertension[J].Pathophysiology,2019,26(3-4):219-226. [10] Navas-Madronal M,Rodriguez C,Kassan M,et al.Enhanced endoplasmic reticulum and mitochondrial stress in abdominal aortic aneurysm[J].Clin Sci (Lond),2019,133(13):1421-1438. [11] Zhang HM,Qiu Y,Zhao G,et al.Cleavage and degradation of EDEM1 promotes coxsackievirus B3 replication via ATF6a-mediated unfolded protein response signalling[J].Cell Microbiol,2020,22(7):13198.