Aberrant hyper-expression of the RNA binding protein GIGYF2 in endothelial cells modulates vascular aging and function
Fanglin Niu,
Zhuozhuo Li,
Yuanyuan Ren,
Zi Li,
Hua Guan,
Yang Li,
Yan Zhang,
Yirong Li,
Junle Yang,
Lu Qian,
Wenzhen Shi,
Xiaobin Fan,
Jinli Li,
Lele Shi,
Yi Yu,
Yuyan Xiong
Affiliations
Fanglin Niu
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, PR China
Zhuozhuo Li
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, PR China
Yuanyuan Ren
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, PR China
Zi Li
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, PR China
Hua Guan
Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi, 710018, PR China
Yang Li
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, PR China
Yan Zhang
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, PR China
Yirong Li
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, PR China
Junle Yang
Department of Radiology, Xi’ an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, PR China
Lu Qian
Department of Endocrinology, Xi’ an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, PR China; Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, PR China
Wenzhen Shi
Medical Research Center, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, PR China; Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, PR China
Xiaobin Fan
Department of Obstetrics and Gynecology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, PR China
Jinli Li
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, PR China
Lele Shi
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, PR China
Yi Yu
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, PR China; Corresponding author. Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, PR China.
Yuyan Xiong
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, PR China; Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, PR China; Corresponding author. Faculty of Life Sciences and Medicine, School of Medicine, Northwest University, Xi'an, Shaanxi, PR China.
Vascular endothelial cells (ECs) senescence plays a crucial role in vascular aging that promotes the initiation and progression of cardiovascular disease. The mutation of Grb10-interacting GYF protein 2 (GIGYF2) is strongly associated with the pathogenesis of aging-related diseases, whereas its role in regulating ECs senescence and dysfunction still remains elusive. In this study, we found aberrant hyperexpression of GIGYF2 in senescent human ECs and aortas of old mice. Silencing GIGYF2 in senescent ECs suppressed eNOS-uncoupling, senescence, and endothelial dysfunction. Conversely, in nonsenescent cells, overexpressing GIGYF2 promoted eNOS-uncoupling, cellular senescence, endothelial dysfunction, and activation of the mTORC1-SK61 pathway, which were ablated by rapamycin or antioxidant N-Acetyl-l-cysteine (NAC). Transcriptome analysis revealed that staufen double-stranded RNA binding protein 1 (STAU1) is remarkably downregulated in the GIGYF2-depleted ECs. STAU1 depletion significantly attenuated GIGYF2-induced cellular senescence, dysfunction, and inflammation in young ECs. Furthermore, we disclosed that GIGYF2 acting as an RNA binding protein (RBP) enhances STAU1 mRNA stability, and that the intron region of the late endosomal/lysosomal adaptor MAPK and mTOR activator 4 (LAMTOR4) could bind to STAU1 protein to upregulate LAMTOR4 expression. Immunofluorescence staining showed that GIGYF2 overexpression promoted the translocation of mTORC1 to lysosome. In the mice model, GIGYF2flox/flox Cdh-Cre+ mice protected aged mice from aging-associated vascular endothelium-dependent relaxation and arterial stiffness. Our work discloses that GIGYF2 serving as an RBP enhances the mRNA stability of STAU1 that upregulates LAMTOR4 expression through binding with its intron region, which activates the mTORC1-S6K1 signaling via recruitment of mTORC1 to the lysosomal membrane, ultimately leading to ECs senescence, dysfunction, and vascular aging. Disrupting the GIGYF2-STAU1-mTORC1 signaling cascade may represent a promising therapeutic approach against vascular aging and aging-related cardiovascular diseases.